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Gemmell JS, Lucke-Wold B. Traditional Chinese medicine and modern technology: Network pharmacology and omics sequencing in gastric cancer. World J Gastrointest Oncol 2025; 17:102077. [DOI: 10.4251/wjgo.v17.i3.102077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/10/2024] [Accepted: 01/02/2025] [Indexed: 02/14/2025] Open
Abstract
In this editorial, we comment on the article by Micucci et al published in the recent issue. We focus on the heterogenous nature of gastric cancer (GC) and the potential benefits of integrating traditional Chinese medicine (TCM) with the modern technology of network pharmacology (NP) and omics sequencing. GC is a heterogenous disease, as it incorporates several biochemical pathways that contribute to pathogenesis. TCM acknowledges the multifactorial, heterogenous nature of disease and utilizes an integrative approach to medicine. NP, a modern philosophy within drug development, integrates traditional knowledge of nutraceuticals and modern technologies to address the complex interactions of pathways within the body. Omics technologies, which is at the core of precision medicine, has allowed for this newfound principle of drug development. Metabolic pathways are better distinguished, leading to more targeted drug development. However, the use of omics technology needs to be employed to better characterize the subtypes of GC. This will allow TCM’s use of nutraceuticals in the application of NP to better target metabolic pathways that may aid in the prevention of GC as well as enhance treatment.
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Affiliation(s)
| | - Brandon Lucke-Wold
- Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States
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Chitale GG, Kulkarni SR, Bapat SA. Chimerism: A whole new perspective in gene regulation. Biochim Biophys Acta Gen Subj 2025; 1869:130767. [PMID: 39855315 DOI: 10.1016/j.bbagen.2025.130767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 01/10/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025]
Abstract
The diversity of molecular entities emerging from a single gene are recognized. Several studies have thus established the cellular role(s) of transcript variants and protein isoforms. A step ahead in challenging the central dogma towards expanding molecular diversity is the identification of fusion genes, chimeric transcripts and chimeric proteins that harbor sequences from more than one gene. The mechanisms for generation of chimeras largely follow similar patterns across all levels of gene regulation but also have interdependence and mutual exclusivity. Whole genome and RNA-seq technologies supported by development of computational algorithms and programs for processing datasets have increasingly enabled the identification of fusion genes and chimeric transcripts, while the discovery of chimeric proteins is as yet more subtle. Earlier thought to be associated with cellular transformation, the contribution of chimeric molecules to normal physiology is also realized and found to influence the expression of their parental genes and regulate cellular pathways. This review offers a collective and comprehensive overview of cellular chimeric entities encompassing the mechanisms involved in their generation, insights on their evolution, functions in gene regulation and their current and novel clinical applications.
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Affiliation(s)
- Gayatri G Chitale
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India
| | - Shweta R Kulkarni
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India
| | - Sharmila A Bapat
- National Centre for Cell Science, Savitribai Phule Pune University, Ganeshkhind, Pune 411007, India.
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Guo X, Liu Y, Wang YT, Liu K, Ding H. Combined BRAF G469A mutation and echinoderm microtubule associated protein like-4-anaplastic lymphoma kinase rearrangement with resistance: A case report and review of literature. World J Clin Oncol 2025; 16:98812. [DOI: 10.5306/wjco.v16.i2.98812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 10/13/2024] [Accepted: 10/24/2024] [Indexed: 12/11/2024] Open
Abstract
BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer (NSCLC) over the past years, some patients with driver mutations have benefited from the targeted molecular therapies. Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC, the availability of several targeted-drugs has been confirmed through a series of clinical trials. But little is clear about the proper strategy in rare BRAF G469A mutation, not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations, which is extremely rare in NSCLC.
CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation. She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.
CONCLUSION Due to the rarity of co-mutations, the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations, but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.
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Affiliation(s)
- Xuan Guo
- Department of Pulmonary and Critical Care Medicine, Yixing People’s Hospital of Jiangsu University, Yixing 214200, Jiangsu Province, China
| | - Yan Liu
- Department of Pulmonary and Critical Care Medicine, Yixing People’s Hospital of Jiangsu University, Yixing 214200, Jiangsu Province, China
| | - Yu-Ting Wang
- Department of Pulmonary and Critical Care Medicine, Yixing People’s Hospital of Jiangsu University, Yixing 214200, Jiangsu Province, China
| | - Kan Liu
- Department of Pulmonary and Critical Care Medicine, Yixing People’s Hospital of Jiangsu University, Yixing 214200, Jiangsu Province, China
| | - Hui Ding
- Department of Pulmonary and Critical Care Medicine, Yixing People’s Hospital of Jiangsu University, Yixing 214200, Jiangsu Province, China
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Sikkema BJ, Baart SJ, Paats MS, Smit EF, Schols AMWJ, Mathijssen RHJ, van Rossum EFC, Dingemans AMC. Body Weight Gain Associated With Alectinib in Patients With ALK+ Non-Small Cell Lung Cancer: Pooled Analysis of Individual Patient Data From Four Prospective Clinical Trials. J Clin Oncol 2025; 43:641-650. [PMID: 39661917 DOI: 10.1200/jco-24-01579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/30/2024] [Accepted: 10/31/2024] [Indexed: 12/13/2024] Open
Abstract
PURPOSE Weight gain is a known adverse event (AE) of alectinib. This study evaluates the progression of actual weight gain over time and explores its association with baseline characteristics. METHODS A pooled analysis of individual patient data from four clinical trials (ALEX, J-ALEX, ALUR, and ML29453) was conducted. Actual weight gain was calculated as the percent change from baseline. A linear mixed model estimated weight change over time and associations between clinical characteristics and weight change. RESULTS Follow-up weights were available for three trials (J-ALEX, ALUR, and ML29453) and missing for ALEX. In total, 2,622 weights were recorded in the first year (N = 302). At baseline, 13.6% of the Japanese population were underweight and 5.0% in the Western population. Actual weight gain of any grade was substantially higher than reported AE rates (49% v 5%), with 18% experiencing ≥10% weight gain (from median 55.6 kg to 64.1 kg). Time on alectinib was positively associated with weight change (β = .37; 95% CI, 0.24 to 0.51; P < .001), corresponding to an average increase of 4.4% over 1 year. Baseline BMI was not associated with weight change in J-ALEX (β = -.090 [95% CI, -0.19 to 0.012]; P = .092) and ALUR/ML29453 (β = -.016 [95% CI, -0.077 to 0.044]; P = .59). Baseline albumin was positively associated with weight change in ALUR/ML29453 (β = .084 [95% CI, 0.027 to 0.14]; P = .0045), although not considered a clinically meaningful predictor. CONCLUSION Weight gain is under-reported as AE in trials. Actual weights showed ≥10% weight gain in 18% of patients. Clinicians should be aware of this AE, emphasizing the importance of timely identification and monitoring weight. Identifying predictors for weight gain remains challenging.
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Affiliation(s)
- Barend J Sikkema
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Sara J Baart
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
- Department of Biostatistics, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marthe S Paats
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Egbert F Smit
- Department of Pulmonary Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Annemie M W J Schols
- Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Elisabeth F C van Rossum
- Department of Internal Medicine, Division of Endocrinology and Obesity Center CGG, Erasmus MC, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Anne-Marie C Dingemans
- Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
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Vincoff S, Goel S, Kholina K, Pulugurta R, Vure P, Chatterjee P. FusOn-pLM: a fusion oncoprotein-specific language model via adjusted rate masking. Nat Commun 2025; 16:1436. [PMID: 39920196 PMCID: PMC11806025 DOI: 10.1038/s41467-025-56745-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 01/24/2025] [Indexed: 02/09/2025] Open
Abstract
Fusion oncoproteins, a class of chimeric proteins arising from chromosomal translocations, are major drivers of various pediatric cancers. These proteins are intrinsically disordered and lack druggable pockets, making them highly challenging therapeutic targets for both small molecule-based and structure-based approaches. Protein language models (pLMs) have recently emerged as powerful tools for capturing physicochemical and functional protein features but have yet to be trained on fusion oncoprotein sequences. We introduce FusOn-pLM, a fine-tuned pLM trained on a newly curated, comprehensive set of fusion oncoprotein sequences, FusOn-DB. Employing a unique cosine-scheduled masked language modeling strategy, FusOn-pLM dynamically adjusts masking rates (15%-40%) to optimize feature extraction and representation quality, surpassing baseline embeddings in fusion-specific tasks, including localization, puncta formation, and disorder prediction. FusOn-pLM uniquely predicts drug-resistant mutations, providing insights for therapeutic design that anticipates resistance mechanisms. In total, FusOn-pLM provides biologically relevant representations for advancing therapeutic discovery in fusion-driven cancers.
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Affiliation(s)
- Sophia Vincoff
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Shrey Goel
- Department of Computer Science, Duke University, Durham, NC, USA
| | - Kseniia Kholina
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Rishab Pulugurta
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Pranay Vure
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Pranam Chatterjee
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
- Department of Computer Science, Duke University, Durham, NC, USA.
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
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Wang M, Liu H, Zhang R, Li R, Qin X, Ning F, Tian L. Small cell lung cancer with EML4-ALK fusion: report of a case responding to ALK TKI and literature review. J Cancer Res Clin Oncol 2025; 151:62. [PMID: 39909915 PMCID: PMC11799027 DOI: 10.1007/s00432-025-06091-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/09/2025] [Indexed: 02/07/2025]
Abstract
PURPOSE With the continuous development and progress of next-generation gene sequencing technology, many types of anaplastic lymphoma kinase (ALK) rearrangement have been discovered. However, in small cell lung cancer (SCLC), ALK rearrangement is extremely rare and there is no standard treatment protocol. By reviewing the literature, we summarized the previously reported cases of ALK-positive SCLC, and discussed the significance of molecular detection. METHOD We report a rare patient with EML4-ALK fusion gene SCLC, a 41-year-old woman with no history of smoking or drinking, who was admitted to the hospital with chest tightness, dyspnea, and cough and sputum. Extensive SCLC (cT4N0M1) was diagnosed after relevant examination and pathological examination. The patient relapsed again six months after receiving first-line chemoradiotherapy. And the patient still developed disease progression (PD) after continued multi-line treatment including chemotherapy, immunotherapy, and anti-vascular therapy. ALK inhibitor is currently being taken orally, and significant clinical response has been achieved. Progression-free survival (PFS) was more than 8 months. RESULT ALK rearrangement of SCLC is rare. The stage IV patient with ALK rearrangement benefit from ALK inhibitors after multiline therapy. CONCLUSION For patients with ALK-positive SCLC, ALK inhibitors may be a reliable treatment option.
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Affiliation(s)
- Mingyue Wang
- Department of Oncology, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China
| | - Hongzhi Liu
- Department of Traumatic Orthopedics, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China
| | - Ruixin Zhang
- Department of Oncology, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China
| | - Runyu Li
- Department of Oncology, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China
| | - Xiaoyu Qin
- Department of Oncology, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China
| | - Fangling Ning
- Department of Oncology, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China.
| | - Lijun Tian
- Department of Oncology, Binzhou Medical University Hospital, Binzhou City, Shandong Province, China.
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Zhao H, Huang S, Wu J, Lu Y, Zou Y, Zeng H, Li C, Wang J, Zhang X, Duan S, Liang W. Efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor in the treatment of patients with advanced non-small cell lung cancer: a systemic review and meta-analysis. Front Immunol 2025; 16:1515027. [PMID: 39981238 PMCID: PMC11839650 DOI: 10.3389/fimmu.2025.1515027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025] Open
Abstract
Introduction The combination of PD-1/PD-L1 inhibitor with CTLA-4 inhibitor for advanced non-small cell lung cancer(NSCLC) is presently a significant area of research, however its clinical application remains contentious. This meta-analysis aimed to assess the efficacy and safety of first-line PD-1/PD-L1 inhibitor in combination with CTLA-4 inhibitor (CP) in the treatment of patients with advanced NSCLC. Methods A systemic search was conducted in four databases (PubMed, Cochrane library, Embase, and Web of Science) from their establishment until January 17, 2024, for randomized controlled trials that investigated the use of the first-line PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor in patients with advanced NSCLC. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were subjected to meta-analyses. Results Totally 7 eligible randomized controlled trials including 4682 people were included. Two comparative analyses were performed: CP versus chemotherapy, CP versus PD-1/PD-L1 inhibitor (P). Compared with the chemotherapy group, CP improved OS (HR: 0.84, 95% CI: 0.75-0.94, p<0.05) but not PFS (HR: 0.94, 95%CI: 0.73-1.20, p = 0.63) or ORR (OR: 1.16, 95% CI: 0.79-1.71, p = 0.45). In terms of toxicity, CP had slightly fewer any AEs compared to chemotherapy (RR: 0.94, 95% CI: 0.91-0.97; p<0.05). Compared to the P group, there was no significant difference in OS (MD: -0,25, 95% CI: -2.47-1.98, p = 0.83), PFS (MD: -0.91, 95% CI: -3.19-1.36, p = 0.43), and ORR (OR:1.05, 95% CI. 0.80-1.36, p = 0.73). Subgroup analysis revealed that CP provided superior OS compared with P in patients with PD-L1 expression < 1%. Conclusion CP was a feasible and safe first-line therapy for patients with advanced NSCLC. Specifically, CP may function as a therapeutic alternative for individuals with low or negative PD-L1 expression, resulting in enhanced long-term outcomes compared to chemotherapy or P. Further randomized controlled trials with prolonged follow-up periods are necessary to validate these results, particularly focusing on efficacy in patients with differing PD-L1 expression levels, to improve the stratified implementation of immunotherapy. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024621116, identifier CRD42024621116.
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Affiliation(s)
- Huimin Zhao
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Shanshan Huang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Jianyu Wu
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Yanlan Lu
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Yue Zou
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Haijian Zeng
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Chunlan Li
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Jin Wang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Xiaochen Zhang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
- Medicine College, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Siliang Duan
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
- Medicine College, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
| | - Weiming Liang
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, Guangxi, China
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Camidge DR, Sugawara S, Kondo M, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, Kudou K, Asato T, Hupf B, Vranceanu F, Fram RJ, Ohe Y, Popat S. Efficacy and safety of brigatinib in patients with ALK TKI-naive advanced ALK+ NSCLC: Integrated analysis of the ALTA-1L and J-ALTA trials. Lung Cancer 2025; 201:108424. [PMID: 39923717 DOI: 10.1016/j.lungcan.2025.108424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/29/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
OBJECTIVES Brigatinib approval as a first-line anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) for advanced ALK+ non-small cell lung cancer (NSCLC) is supported by results of a non-Japanese global phase 3 trial (ALTA-1L) and a separate phase 2 trial conducted in Japan (J-ALTA). To evaluate outcomes in a larger global patient population, we conducted an integrated analysis of pooled efficacy and safety data from ALTA-1L and J-ALTA. MATERIALS AND METHODS ALTA-1L (NCT02737501) and J-ALTA (NCT03410108) were open-label, multicenter studies of patients with advanced or metastatic ALK+ NSCLC. ALTA-1L and an expansion cohort of J-ALTA enrolled patients who were ALK TKI naive. Patients with stable or asymptomatic brain metastases were allowed. Brigatinib 180 mg was administered once daily following 7-day lead-in at 90 mg. Primary endpoints were blinded independent review committee (IRC)-assessed progression-free survival (PFS) in ALTA-1L and IRC-assessed 12-month PFS in the J-ALTA ALK TKI-naive cohort. Secondary endpoints included IRC-assessed objective response rate (ORR), duration of response (DOR), intracranial ORR, overall survival (OS), and safety. RESULTS Overall, 169 patients were allocated to brigatinib in ALTA-1L (n = 137) or J-ALTA (n = 32). In the pooled population (median follow-up: 35.8 months), 34 % of patients were aged ≥65 years, 28 % had baseline brain metastases, and 26 % had received prior chemotherapy. Median PFS by IRC was 29.3 months (95 % CI: 23.9-44.7). Confirmed ORR was 79 % (95 % CI, 72 %-85 %). Median DOR was 38.1 months. Intracranial ORR was 66 % in patients with any brain metastases and 70 % in patients with measurable brain metastases. Three-year OS was 74 %. Grade 3/4 adverse events occurred in 74 % of patients, most commonly increased blood creatine phosphokinase (31 %), hypertension (18 %), and increased lipase (16 %). CONCLUSION Brigatinib demonstrated clinically meaningful systemic and intracranial efficacy in patients with ALK TKI-naive ALK+ NSCLC. Safety results were consistent with the known profile for brigatinib.
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Affiliation(s)
| | | | - Masashi Kondo
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Japan
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Myung-Ju Ahn
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - James C H Yang
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | | | - Maximilian J Hochmair
- Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Department of Respiratory and Critical Care Medicine, Krankenhaus Nord, Klinik Floridsdorf, Vienna, Austria
| | - Ki Hyeong Lee
- Chungbuk National University Hospital, Cheongju, South Korea
| | - Angelo Delmonte
- IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST), Meldola, Italy
| | - Kentarou Kudou
- Biostatistics, Japan Development Center, Takeda Pharmaceutical Company Limited, Osaka, Japan
| | - Takayuki Asato
- Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, Osaka, Japan
| | - Bradley Hupf
- Takeda Development Center Americas, Inc., Cambridge, MA, USA
| | | | - Robert J Fram
- Takeda Development Center Americas, Inc., Cambridge, MA, USA
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Sanjay Popat
- Royal Marsden Hospital, London, England, United Kingdom
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Utsumi T, Mizuta H, Seto Y, Uchibori K, Nishio M, Okamoto I, Katayama R. AXL-Mediated Drug Resistance in ALK-Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts. Cancer Sci 2025. [PMID: 39904499 DOI: 10.1111/cas.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/10/2025] [Accepted: 01/22/2025] [Indexed: 02/06/2025] Open
Abstract
Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) shows marked tumor shrinkage by ALK-tyrosine kinase inhibitors (TKIs). However, tumors almost inevitably relapse owing to the development of acquired resistance. Resistance mechanisms include secondary ALK mutations and the activation of bypass pathways, such as cMET, cKIT, or EGFR, though some remain unknown. In this study, we analyzed alectinib-resistant patient samples and identified a significant increase in AXL expression in the tumor, and a high level of GAS6, the ligand for AXL, in the pleural effusion. AXL-overexpressing H3122 ALK-rearranged NSCLC cells exhibited partial resistance to alectinib, which was enhanced by GAS6 supplementation but could be overcome by the ALK/AXL inhibitor gilteritinib. Moreover, GAS6-overexpressing NIH3T3 cells and AXL-expressing H3122 cells were subcutaneously injected into the left and right sides of nude mice simultaneously, followed by alectinib treatment. The supply of GAS6 from NIH3T3 may have accelerated tumor relapse under alectinib treatment. However, even without GAS6-overexpressing NIH3T3, AXL-overexpressing H3122 tumor relapsed within 1 month possibly due to increased host mouse Gas6 expression. Single-cell RNA sequencing revealed that specific cancer-associated fibroblasts (CAFs) and a subset of tumor-associated macrophages (TAMs) are the primary sources of Gas6 in the tumor microenvironment (TME). During alectinib treatment, TAMs increased their infiltration into the TME, whereas CAFs altered their expression patterns, substantially upregulating Mmp11. These findings suggest that AXL expression in resistant cancer cells, combined with increased Gas6 production in the TME, contributes to enhanced ALK-TKI resistance.
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Affiliation(s)
- Takahiro Utsumi
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hayato Mizuta
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Kanagawa, Japan
| | - Yosuke Seto
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ken Uchibori
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryohei Katayama
- Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
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10
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Poei D, Ali S, Thomas JS, Nieva JJ, Hsu RC. Real-World Incidence of Anaplastic Lymphoma Kinase Alterations in Hispanics with Non-Small Cell Lung Cancer at a Large Academic Institution in Los Angeles. CANCER RESEARCH COMMUNICATIONS 2025; 5:277-286. [PMID: 39807831 PMCID: PMC11808653 DOI: 10.1158/2767-9764.crc-24-0504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/09/2024] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
SIGNIFICANCE This study identified a higher incidence of ALK alterations in Hispanic patients with NSCLC (12.76%) compared with that in non-Hispanic patients (5.36%) treated at a large academic center in Los Angeles, highlighting the impact of race on molecular alteration profiles and emphasizing the need to increase access to molecular analyses for this population. The variability in mutational alterations may be influenced by biological and environmental factors.
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Affiliation(s)
- Darin Poei
- Department of Medicine, University of Southern California, Los Angeles, California
| | - Sana Ali
- Division of Medical Oncology, Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
| | - Jacob S. Thomas
- Division of Medical Oncology, Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
| | - Jorge J. Nieva
- Division of Medical Oncology, Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
| | - Robert C. Hsu
- Division of Medical Oncology, Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
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11
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Ka M, Matsumoto Y, Ando T, Hinata M, Xi Q, Sugiura Y, Iida T, Nakagawa N, Tokunaga M, Watanabe K, Kawakami M, Ushiku T, Sato M, Oda K, Kage H. Integrin-α5 expression and its role in non-small cell lung cancer progression. Cancer Sci 2025; 116:406-419. [PMID: 39581761 PMCID: PMC11786322 DOI: 10.1111/cas.16416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024] Open
Abstract
Integrins are transmembrane receptors that facilitate cell adhesion to the extracellular matrix and neighboring cells. Aberrant expression of integrins has been associated with tumor progression and metastasis in various cancer types. Integrin alpha-5 (ITGA5) is an integrin subtype that serves as a receptor for fibronectin, fibrinogen, and fibrillin-1. The purpose of this study was to elucidate how ITGA5 expression plays a role in human non-small cell lung cancer (NSCLC). Our clinical data, along with data retrieved from The Cancer Genome Database (TCGA), revealed that high ITGA5 expression in NSCLC patients was associated with a lower recurrence-free survival and overall survival. In our in vitro functional assays, ITGA5 overexpression in human NSCLC cell lines resulted in increased cell size, adhesion, and migration properties, while knockdown of ITGA5 restored the phenotypes. Correspondingly, knockdown and inhibition of ITGA5 in endogenously high-expressing NSCLC cell lines resulted in decreased cell size, adhesion, migration, and proliferation. The antiproliferative effect was also confirmed by a reduction in Ki-67 without discernible changes in apoptosis. Collectively, these findings reveal the significant role of ITGA5 in various functional behaviors in NSCLC, providing a potential therapeutic target for NSCLC patients with high ITGA5 expression.
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Affiliation(s)
- Mirei Ka
- Division of Integrative GenomicsThe University of TokyoTokyoJapan
| | - Yoko Matsumoto
- Department of Respiratory MedicineThe University of TokyoTokyoJapan
| | - Takahiro Ando
- Department of Respiratory MedicineThe University of TokyoTokyoJapan
| | | | - Qian Xi
- Division of Integrative GenomicsThe University of TokyoTokyoJapan
| | - Yuriko Sugiura
- Department of Respiratory MedicineThe University of TokyoTokyoJapan
| | - Takahiro Iida
- Department of Thoracic SurgeryThe University of TokyoTokyoJapan
| | - Natsuki Nakagawa
- Department of Respiratory MedicineThe University of TokyoTokyoJapan
| | | | - Kousuke Watanabe
- Next‐Generation Precision Medicine Development Laboratory, Graduate School of MedicineThe University of TokyoTokyoJapan
| | | | - Tetsuo Ushiku
- Department of PathologyThe University of TokyoTokyoJapan
| | - Masaaki Sato
- Department of Thoracic SurgeryThe University of TokyoTokyoJapan
| | - Katsutoshi Oda
- Division of Integrative GenomicsThe University of TokyoTokyoJapan
| | - Hidenori Kage
- Department of Respiratory MedicineThe University of TokyoTokyoJapan
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12
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Wang S, Wang Y, Wu X, Yang L, Zhang X. Patients outcomes in lung adenocarcinoma transforming to small-cell lung cancer after tyrosine kinase inhibitor therapy. World J Surg Oncol 2025; 23:34. [PMID: 39893475 PMCID: PMC11787757 DOI: 10.1186/s12957-025-03687-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 01/24/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) transforming to small cell lung cancer (SCLC) is one of the mechanisms of resistance to tyrosine kinase inhibitors (TKIs). Cases of NSCLC transforming into SCLC have been discovered. However, we lack concentrated data on the characteristics of this population and the transformed SCLC to aid our insight of the biology and clinical value of NSCLC transforming with positive. METHODS We systematically reviewed the published literatures and summarized the pathological and clinical characteristics, and the prognosis, of published cases. RESULTS 140 patients with lung adenocarcinoma (LUAD) were included in this study, with a median age of 56.8 years. The median time from the first diagnosis of LUAD transforming to SCLC (ttSCLC) was 20.0 months. The median overall survival (mOS) after the diagnosis of SCLC was 11.0 months (95% CI, 7.41 to 14.59 months). In the univariate analysis, ever smoking (either former or current) was a promising predictor of a shorter ttSCLC (HR, 1.73; 95% CI, 1.14 to 2.62; P = 0.010). TKIs therapy administered as a second line and beyond treatment was related to a significant delay in SCLC onset compared to first-line therapy (HR, 0.62; 95% CI, 0.40 to 0.96; P = 0.031). The median progression-free survival (mPFS) on first-line platinum plus etoposide after the conversion to SCLC was 3.0 months. Female appeared to be related to worse outcomes after transformation of SCLC. CONCLUSION Transformed SCLC exhibited poor response to primary SCLC classic chemotherapy and immunotherapy. It carries a worse prognosis. Exploring novel therapeutic strategies for transformed SCLC is imperative.
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Affiliation(s)
- Shuai Wang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China
| | - Yongsen Wang
- Department of Molecular Pathology, Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xuan Wu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China
| | - Li Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China
| | - Xiaoju Zhang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, No. 7, Weiwu Road, Zhengzhou, 450000, China.
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13
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Luo W, Zheng J, Hei M, Jiang Y, Su B. Superficial ALK-rearranged myxoid spindle cell neoplasms: Clinicopathologic and molecular analysis of two cases and a review of the literature. Ann Diagn Pathol 2025; 74:152395. [PMID: 39550857 DOI: 10.1016/j.anndiagpath.2024.152395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 11/19/2024]
Abstract
Superficial anaplastic lymphoma kinase (ALK)-rearranged myxoid spindle cell neoplasms are a recently identified subtype of cutaneous soft tissue tumors, distinct for their co-expression of CD34 and S100 and characterized by ALK gene rearrangements. Although 72 cases have been reported primarily as isolated case reports, this tumor subtype has yet to be included in the WHO classification of soft tissue tumors, underscoring the need for further study. In this study, we diagnosed two additional cases, both arising in the dermis and subcutaneous tissue. These tumors exhibited characteristic pathological features, including linear or concentric whorl patterns, prominent myxoid and collagenized stroma, mild cellular atypia, and rare mitotic activity. The presence of infiltrative margins and the potential for recurrence after surgery suggest at least locally aggressive clinical behavior. Immunohistochemically, the tumors diffusely expressed S100 and CD34, with strong ALK-D5F3 positivity, confirmed by ALK gene rearrangement. These findings further expand the clinical and pathological spectrum of ALK-rearranged neoplasms and highlight the need for continued research on their biological behavior and classification.
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Affiliation(s)
- Wenwen Luo
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China
| | - Jinyue Zheng
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China
| | - Mengying Hei
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China
| | - Ye Jiang
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China.
| | - Bojin Su
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, PR China.
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14
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Apsel Winger B, Dowd CF, Shimano KA, Devine WP, Mathes E, Frieden I, Schaefer C, Kothari A. Effective Use of ALK Inhibitors in EML4::ALK-Positive Lymphatic Malformations. Pediatr Blood Cancer 2025; 72:e31441. [PMID: 39529238 DOI: 10.1002/pbc.31441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/08/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024]
Abstract
Genetically targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK-positive LMs, one with Gorham Stout disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly targeted therapies for LMs.
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Affiliation(s)
- Beth Apsel Winger
- Department of Clinical Pharmacy, UCSF, San Francisco, California, USA
- Division of Pediatric Hematology, UCSF, San Francisco, California, USA
| | - Christopher F Dowd
- Division of Interventional Neuroradiology, UCSF, San Francisco, California, USA
| | - Kristin A Shimano
- Division of Pediatric Hematology, UCSF, San Francisco, California, USA
| | - W Patrick Devine
- Department of Anatomic Pathology, UCSF, San Francisco, California, USA
| | - Erin Mathes
- Department of Dermatology, UCSF, San Francisco, California, USA
| | - Ilona Frieden
- Department of Dermatology, UCSF, San Francisco, California, USA
| | - Carrie Schaefer
- Department of Radiology, Phoenix Children's Hospital, Phoenix, Arizona, USA
| | - Alok Kothari
- Division of Pediatric Hematology/Oncology, Phoenix Children's Hospital, Phoenix, Arizona, USA
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15
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Graciotti M, Kandalaft LE. Vaccines for cancer prevention: exploring opportunities and navigating challenges. Nat Rev Drug Discov 2025; 24:134-150. [PMID: 39622986 DOI: 10.1038/s41573-024-01081-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 02/06/2025]
Abstract
Improved understanding of cancer immunology has gradually brought increasing attention towards cancer-preventive vaccines as an important tool in the fight against cancer. The aim of this approach is to reduce cancer occurrence by inducing a specific immune response targeting tumours at an early stage before they can fully develop. The great advantage of preventive cancer vaccines lies in the potential to harness a less-compromised immune system in vaccine recipients before their immune responses become affected by the advanced status of the disease itself or by aggressive treatments such as chemotherapy. Successful implementation of immunoprevention against oncogenic viruses such as hepatitis B and papillomavirus has led to a dramatic decrease in virally induced cancers. Extending this approach to other cancers holds great promise but remains a major challenge. Here, we provide a comprehensive review of preclinical evidence supporting this approach, encouraging results from pioneering clinical studies as well as a discussion on the key aspects and open questions to address in order to design potent prophylactic cancer vaccines in the near future.
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Affiliation(s)
- Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Lana E Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
- Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland.
- AGORA Cancer Research Center, Lausanne, Lausanne, Switzerland.
- Swiss Medical Network, Genolier Innovation Network, Genolier Clinic, Genolier, Switzerland.
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16
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Shiraishi N, Takahama T, Sakai K, Tanaka K, Nakagawa Y, Kanemura H, Nakayama T, Kawanaka Y, Kurosaki T, Suzuki S, Iwasa T, Tanizaki J, Inagaki C, Yonesaka K, Fukuoka K, Mitsudomi T, Nishio K, Hayashi H, Nakagawa K. Detection of Overlooked Rare EGFR Mutations in Non-small Cell Lung Cancer Using Multigene Testing. Thorac Cancer 2025; 16:e70007. [PMID: 39947926 PMCID: PMC11825211 DOI: 10.1111/1759-7714.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Recognizing rare molecular variants of driver mutations poses a challenge in precision oncology, particularly for treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to determine whether Oncomine Dx Target Test Multi-CDx System (ODxTT), the most widely used genetic test for NSCLC in Japan, potentially overlooks druggable EGFR mutations. MATERIALS AND METHODS Among 418 patients who underwent molecular testing using ODxTT at our hospital, 267 were diagnosed with adenocarcinoma. No mutations were reported in 82 of these cases. For these 82 cases, we searched for EGFR mutations in exons 18-21 by examining the binary alignment map file. Once a mutation was identified, its pathological significance was evaluated using the ClinVar database to determine whether ODxTT had overlooked any actionable EGFR mutations. RESULTS Mutations in EGFR exons 19 and 18 were identified in six and four cases, respectively. Three, six, and none of these variants were detectable using the Cobas EGFR Mutation Test v2, Lung Cancer Compact Panel, and Amoy Dx, respectively. Of the 10 patients, five were subsequently treated with EGFR TKI; three showed partial response, one had stable disease, and one had progressive disease. CONCLUSIONS ODxTT failed to identify 10 actionable EGFR mutations, accounting for 12.2% (10/82) of the cases initially reported as not carrying actionable mutations. Therefore, comprehensive genomic profiling should be actively performed early in cases with high clinical suspicion of EGFR mutations.
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Affiliation(s)
| | - Takayuki Takahama
- Genome Medical CenterKindai University HospitalOsakaJapan
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Kazuko Sakai
- Department of Genome BiologyKindai University Faculty of MedicineOsakaJapan
| | - Kaoru Tanaka
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | | | - Hiroaki Kanemura
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Tomohiro Nakayama
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
- Department of Medical OncologyKishiwada City HospitalOsakaJapan
| | - Yusuke Kawanaka
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Takashi Kurosaki
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Shinichiro Suzuki
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Tsutomu Iwasa
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Junko Tanizaki
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Chiaki Inagaki
- Genome Medical CenterKindai University HospitalOsakaJapan
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Kimio Yonesaka
- Genome Medical CenterKindai University HospitalOsakaJapan
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Kazuya Fukuoka
- Genome Medical CenterKindai University HospitalOsakaJapan
- Clinical Research CenterKindai University HospitalOsakaJapan
| | - Tetsuya Mitsudomi
- Izumi City General HospitalOsakaJapan
- Faculty of MedicineKindai University HospitalSayamaJapan
| | - Kazuto Nishio
- Department of Genome BiologyKindai University Faculty of MedicineOsakaJapan
| | - Hidetoshi Hayashi
- Department of Medical OncologyKindai University Faculty of MedicineOsakaJapan
| | - Kazuhiko Nakagawa
- Genome Medical CenterKindai University HospitalOsakaJapan
- Cancer CenterKindai University HospitalOsakaJapan
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17
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Waliany S, Lin JJ, Gainor JF. Evolution of first versus next-line targeted therapies for metastatic non-small cell lung cancer. Trends Cancer 2025:S2405-8033(25)00006-8. [PMID: 39890507 DOI: 10.1016/j.trecan.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/21/2024] [Accepted: 01/10/2025] [Indexed: 02/03/2025]
Abstract
The expanding armamentarium of targeted therapies has revolutionized treatment for metastatic oncogene-addicted lung cancers. For multiple subsets, such as those harboring EGFR mutations and fusions in ALK or ROS1, successive generation of increasingly potent, selective, and brain-penetrating targeted therapies have shifted the treatment paradigm towards preferential first-line use of next-generation drugs. This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.
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Affiliation(s)
- Sarah Waliany
- Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jessica J Lin
- Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Justin F Gainor
- Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
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18
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Schneider JL, Kurmi K, Dai Y, Dhiman I, Joshi S, Gassaway BM, Johnson CW, Jones N, Li Z, Joschko CP, Fujino T, Paulo JA, Yoda S, Baquer G, Ruiz D, Stopka SA, Kelley L, Do A, Mino-Kenudson M, Sequist LV, Lin JJ, Agar NYR, Gygi SP, Haigis KM, Hata AN, Haigis MC. GUK1 activation is a metabolic liability in lung cancer. Cell 2025:S0092-8674(25)00093-5. [PMID: 39919745 DOI: 10.1016/j.cell.2025.01.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/14/2024] [Accepted: 01/15/2025] [Indexed: 02/09/2025]
Abstract
Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.
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Affiliation(s)
- Jaime L Schneider
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
| | - Kiran Kurmi
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Yutong Dai
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Boston, MA, USA
| | - Ishita Dhiman
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Shakchhi Joshi
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Brandon M Gassaway
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | | | - Nicole Jones
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Zongyu Li
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Christian P Joschko
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Toshio Fujino
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Joao A Paulo
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Satoshi Yoda
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Gerard Baquer
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Daniela Ruiz
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sylwia A Stopka
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Liam Kelley
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Andrew Do
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Lecia V Sequist
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jessica J Lin
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Nathalie Y R Agar
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Steven P Gygi
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Kevin M Haigis
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Aaron N Hata
- Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Marcia C Haigis
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
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19
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Borkhataria CH, Sharma S, Vaja P, Tank C, Mori D, Patel K, Kyada A. Quality management, ethical considerations, and emerging challenges in genomics and biobanking: A comprehensive review. Clin Chim Acta 2025; 569:120161. [PMID: 39864572 DOI: 10.1016/j.cca.2025.120161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 01/28/2025]
Abstract
The integration of genomics into personalized medicine has the potential to transform healthcare by customizing treatments according to individual genetic profiles. This paper examines the diverse applications of genomics, including the identification of disease susceptibility, improvement of diagnostic methods, optimization of drug therapies, and monitoring of treatment responses. It also explores the expanding global market for genetic testing and the increasing implementation of whole-genome sequencing in clinical practice, with a focus on pilot programs that are advancing comprehensive genomic analysis. Despite challenges such as high costs, data interpretation complexities, and ethical concerns, significant efforts are being made to address these issues. Additionally, the creation of biobanks as vital resources for preserving high-quality biosamples and supporting research highlights the critical need for infrastructure development in genomics. By fostering interdisciplinary collaboration and establishing robust ethical and regulatory frameworks, personalized medicine can ensure equitable access to tailored therapies and enhance health outcomes for everyone. This abstract provides an overview of the transformative potential of genomics and personalized medicine in ushering in a new era of precision healthcare.
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Affiliation(s)
| | - Shweta Sharma
- B K Mody Government Pharmacy College Rajkot Gujarat India
| | - Payal Vaja
- School of Pharmacy, Dr. Subhash University Junagadh Gujarat India
| | | | - Dhaval Mori
- B K Mody Government Pharmacy College Rajkot Gujarat India
| | | | - Ashishkumar Kyada
- Department of Pharmaceutical Sciences, Marwadi University Rajkot Gujarat India
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20
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Heo Y, Kim WJ, Cho YJ, Jung JW, Kim NS, Choi IY. Advances in cancer genomics and precision oncology. Genes Genomics 2025:10.1007/s13258-024-01614-7. [PMID: 39849190 DOI: 10.1007/s13258-024-01614-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/27/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Next-generation sequencing has revolutionized genome science over the last two decades. Indeed, the wealth of sequence information on our genome has deepened our understanding on cancer. Cancer is a genetic disease caused by genetic or epigenetic alternations that affect the expression of genes that control cell functions, particularly cell growth and division. Utilization of next-generation sequencing in cancer gene panels has enabled the identification of actionable gene alterations in cancer patients to guide personalized precision medicine. OBJECTIVE The aim is to provide information that can identify actionable gene alterations, enabling personalized precision medicine for cancer patients. RESULTS & DISCUSSION Equipped with next-generation sequencing techniques, international collaboration programs on cancer genomics have identified numerous mutations, gene fusions, microsatellite variations, copy number variations, and epigenetics changes that promote the transformation of normal cells into tumors. Cancer classification has traditionally been based on cell type or tissue-of-origin and the morphological characteristics of the cancer. However, interactive genomic analyses have currently reclassified cancers based on systemic molecular-based taxonomy. Although all cancer-causing genes and mechanisms have yet to be completely understood or identified, personalized or precision medicine is now currently possible for some forms of cancer. Unlike the "one-size-fits-all" approach of traditional medicine, precision medicine allows for customized or personalized treatment based on genomic information. CONCLUSION Despite the availability of numerous cancer gene panels, technological innovation in genomics and expansion of knowledge on the cancer genome will allow precision oncology to manage even more types of cancers.
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Affiliation(s)
- Yonjong Heo
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, Gangwon, Republic of Korea
| | - Woo-Jin Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, 24341, Gangwon, Republic of Korea
| | - Yong-Joon Cho
- Department of Molecular Bioscience, Kangwon National University, Chuncheon, 24341, Republic of Korea
- Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Jae-Won Jung
- Genetic Sciences Group, Thermo Fisher Scientific Solutions Korea Co., Ltd., Seoul, 06349, Republic of Korea
| | - Nam-Soo Kim
- Department of Molecular Bioscience, Kangwon National University, Chuncheon, 24341, Republic of Korea.
- NBIT Co., Ltd., Chuncheon, 24341, Republic of Korea.
| | - Ik-Young Choi
- Department of Smart Farm and Agricultural Industry, Kangwon National University, Chuncheon, 24341, Republic of Korea.
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21
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Yi GZ, Zhang HY, Que TS, Qu SQ, Li ZY, Qi ST, Feng WY, Huang GL. Identification of the clinical and genetic characteristics of gliomas with gene fusions by integrated genomic and transcriptomic analysis. Eur J Med Res 2025; 30:49. [PMID: 39849652 PMCID: PMC11755825 DOI: 10.1186/s40001-025-02306-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 01/16/2025] [Indexed: 01/25/2025] Open
Abstract
The identification of oncogenic gene fusions in diffuse gliomas may serve as potential therapeutic targets and prognostic indicators, representing a novel strategy for treating gliomas consistent with the principles of personalized medicine. This study identified detectable oncogene fusions in glioma patients through an integrated analysis of genomic and transcriptomic data, which encompassed whole exon sequencing and next-generation RNA sequencing. In addition, this study also conducted a comparison of the genetic characteristics, tumor microenvironment, mutation burden and survival between glioma patients with or without gene fusions. A total of 68 glioma patients were enrolled in this study, including glioblastoma (GBM), low grade glioma (LGG) and diffuse midline glioma (DMG). 14 cases of GBM patients (51.9%, 14/27) were found to harbor the following 70 oncogenic gene fusions: ROS1 (n = 8), NTRK (n = 5), KIF5 (n = 5), RET (n = 3) and other infrequent gene fusions (n = 49). A total of 11 gene fusions were identified in 8 LGG patients (32.0%, 8/25) and seven gene fusions were identified in one DMG patient (16.7%, 1/6). In GBM patient group, five genes including HOXA3, ACTB, CDK5, GNA12 and CARD11 exhibited a statistically significant higher copy number amplification frequency in the GBM group without gene fusions compared to that in the GBM group with gene fusions. In LGG patient group, CDK5 gene was also found to exhibit a statistically significant higher amplification frequency in the LGG group without gene fusions. In addition, KMT2D exhibited a statistically significant higher mutation frequency in the LGG group with gene fusions compared to that in the LGG group without gene fusions. Comparison of the other genetic characteristics including immune cell infiltration score, tumor mutation burden (TMB), and microsatellite instability (MSI). The results showed no statistically significant differences were observed between fusion and non-fusion group of GBM and LGG. The survival analysis revealed that GBM patients without gene fusions exhibited a longer median survival (737 days) compared to GBM patients with gene fusions (642 days), but without a statistical significancy. Our study has identified a set of gene fusions present in gliomas, including a number of novel gene fusions that have not been previously reported. We have also elucidated the underlying genetic characteristics of glioma with gene fusions. Collectively, our findings have the potential to inform future clinical treatment strategies for patients with glioma.
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Affiliation(s)
- Guo-Zhong Yi
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Hua-Yang Zhang
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Tian-Shi Que
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Shan-Qiang Qu
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Zhi-Yong Li
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Song-Tao Qi
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, People's Republic of China
- The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Wen-Yan Feng
- Department of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
| | - Guang-Long Huang
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou Avenue North No.1838, Guangzhou, 510515, Guangdong, People's Republic of China.
- Nanfang Glioma Center, Guangzhou, 510515, Guangdong, People's Republic of China.
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22
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Mina SA, Shanshal M, Leventakos K, Parikh K. Emerging Targeted Therapies in Non-Small-Cell Lung Cancer (NSCLC). Cancers (Basel) 2025; 17:353. [PMID: 39941723 PMCID: PMC11816067 DOI: 10.3390/cancers17030353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/13/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.
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Affiliation(s)
- Syeda A. Mina
- Division of Hematology and Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | | | | | - Kaushal Parikh
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
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23
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Watanabe T, Kidoguchi K, Kimura S. Treating Hematological Malignancies With OR-2100, an Orally Bioavailable Prodrug of Decitabine. Cancer Sci 2025. [PMID: 39837580 DOI: 10.1111/cas.16452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/06/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
DNA methylation is an enzyme-driven epigenetic modification that must be precisely regulated to maintain cellular homeostasis. Aberrant methylation status, especially hypermethylation of the promoter sites of tumor-suppressor genes, is observed in human malignancies and is a proven target for cancer therapy. The first-generation DNA demethylating agents, azacitidine and decitabine, are widely used for treating several hematological malignancies. In addition, orally bioavailable prodrugs of azacitidine and decitabine have recently been approved by the FDA. We have developed a silylated derivative of decitabine, OR-2100, which is resistant to degradation by cytidine deaminase and orally bioavailable. It has efficacy against several human hematological malignancies in xenograft mouse models with less hematotoxicity than decitabine. Since DNA demethylating agents are combined with molecularly targeted drugs in clinical use and trials, we think that the less hematotoxic profile of OR-2100 makes it suitable for use as a combination therapy. In this article, we review the therapeutic approach in hematological malignancies with the DNA demethylating agent OR-2100.
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Affiliation(s)
- Tatsuro Watanabe
- Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan
| | - Keisuke Kidoguchi
- Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Shinya Kimura
- Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
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24
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Melosky B, Juergens RA, Banerji S, Sacher A, Wheatley-Price P, Snow S, Tsao MS, Leighl NB, Martins I, Cheema P, Liu G, Chu QSC. The continually evolving landscape of novel therapies in oncogene-driven advanced non-small-cell lung cancer. Ther Adv Med Oncol 2025; 17:17588359241308784. [PMID: 39776537 PMCID: PMC11705342 DOI: 10.1177/17588359241308784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
Non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease that is frequently associated with a host of known oncogenic alterations. Advances in molecular diagnostics and drug development have facilitated the targeting of novel alterations such that the majority of NSCLC patients have driver mutations that are now clinically actionable. The goal of this review is to gain insights into clinical research and development principles by summary, analysis, and discussion of data on agents targeting known alterations in oncogene-driven, advanced NSCLC beyond those in the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK). A search of published and presented literature was conducted to identify prospective trials and integrated analyses reporting outcomes for agents targeting driver gene alterations (except those in EGFR and ALK) in molecularly selected, advanced NSCLC. Clinical efficacy data were extracted from eligible reports and summarized in text and tables. Findings show that research into alteration-directed therapies in oncogene-driven, advanced NSCLC is an extremely active research field. Ongoing research focuses on the expansion of new agents targeting both previously identified targets (particularly hepatocyte growth factor receptor (MET), human epidermal growth factor receptor 2 (HER2), and Kirsten rat sarcoma viral oncogene homolog (KRAS)) as well as novel, potentially actionable targets (such as neuregulin-1 (NRG1) and phosphatidylinositol 3-kinase (PI3K)). The refinement of biomarker selection criteria and the development of more selective and potent agents are allowing for increasingly specific and effective therapies and the expansion of clinically actionable alterations. Clinical advances in this field have resulted in a large number of regulatory approvals over the last 3 years. Future developments should focus on the continued application of alteration therapy matching principles and the exploration of novel ways to target oncogene-driven NSCLC.
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Affiliation(s)
- Barbara Melosky
- Medical Oncology, BC Cancer Agency—Vancouver, University of British Columbia, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada
| | | | - Shantanu Banerji
- Paul Albrechtsen Research Institute, CancerCare Manitoba, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Adrian Sacher
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Paul Wheatley-Price
- Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - Stephanie Snow
- QEII Health Sciences Centre, Dalhousie University, Halifax, NS, Canada
| | - Ming-Sound Tsao
- University Health Network and Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Natasha B. Leighl
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | | | - Parneet Cheema
- William Osler Health System, University of Toronto, Brampton, ON, Canada
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Quincy S. C. Chu
- Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
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25
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Andrijanova A, Bugovecka L, Isajevs S, Erts D, Malinovskis U, Liepins A. Machine Learning for Lung Cancer Subtype Classification: Combining Clinical, Histopathological, and Biophysical Features. Diagnostics (Basel) 2025; 15:127. [PMID: 39857011 PMCID: PMC11764335 DOI: 10.3390/diagnostics15020127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/16/2024] [Accepted: 12/20/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Despite advances in diagnostic techniques, accurate classification of lung cancer subtypes remains crucial for treatment planning. Traditional methods like genomic studies face limitations such as high cost and complexity. This study investigates whether integrating atomic force microscopy (AFM) measurements with conventional clinical and histopathological data can improve lung cancer subtype classification. Methods: We developed and analyzed a novel dataset combining clinical, histopathological, and AFM-derived biophysical characteristics from 37 lung cancer patients. Various machine learning techniques were evaluated, with a focus on Bayesian Networks due to their ability to handle complex data with missing values. Leave-One-Out Cross-Validation was employed to assess model performance. Results: The integration of biophysical features improved classification accuracy from 86.49% to 89.19% using a data-driven Bayesian Network model, though this improvement was not statistically significant (p = 1.0). Four key features were identified as highly predictive: sex, vascular invasion, perineural invasion, and ALK mutation. A simplified model using only these features achieved identical performance with significantly reduced complexity (BIC 51.931 vs. 268.586). Conclusions: While AFM-derived measurements showed promise for enhancing lung cancer subtype classification, larger datasets are needed to fully validate their impact. Our findings demonstrate the feasibility of incorporating biophysical measurements into cancer classification frameworks and identify the most predictive features for accurate diagnosis. Further research with expanded datasets is needed to validate these findings.
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Affiliation(s)
| | - Lasma Bugovecka
- Institute of Chemical Physics, Faculty of Science and Technology, University of Latvia, Jelgavas Street 1, LV-1004 Riga, Latvia; (L.B.); (D.E.); (U.M.)
| | - Sergejs Isajevs
- Faculty of Medicine and Life Sciences, University of Latvia, Jelgavas Street 3, LV-1004 Riga, Latvia;
| | - Donats Erts
- Institute of Chemical Physics, Faculty of Science and Technology, University of Latvia, Jelgavas Street 1, LV-1004 Riga, Latvia; (L.B.); (D.E.); (U.M.)
| | - Uldis Malinovskis
- Institute of Chemical Physics, Faculty of Science and Technology, University of Latvia, Jelgavas Street 1, LV-1004 Riga, Latvia; (L.B.); (D.E.); (U.M.)
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26
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Nassar AH, Jayakrishnan R, Feng J, Shepherd F, Adib E, Cheung JM, Lin JJ, Liu Y, Lin SH, Parikh K, Sridhar A, Shakya P, Dilling TJ, Kaldas D, Gray JE, Lobachov A, Bar J, Luders H, Grohe C, Gupta S, Leal T, Fitzgerald B, Crowley F, Fujiwara Y, Marron TU, Wilgucki M, Reuss J, Chen L, Sankar K, Aredo JV, Neal JW, Wakelee HA, Thummalapalli R, Yu H, Whitaker R, Velazquez A, Ragavan M, Cortellini A, Kwiatkowski DJ, Naqash AR, Goldberg SB, Kim SY. Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC. J Thorac Oncol 2025; 20:109-118. [PMID: 39260522 DOI: 10.1016/j.jtho.2024.09.1379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/19/2024] [Accepted: 09/01/2024] [Indexed: 09/13/2024]
Abstract
INTRODUCTION Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation. METHODS We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis. RESULTS A total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49-67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7- not reached) versus durvalumab (11.3 mo, 95% CI: 8.9-18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026-0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4-10.6, HR = 0.04, 95% CI: 0.009-0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19-0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab. CONCLUSIONS Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.
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Affiliation(s)
- Amin H Nassar
- Yale University School of Medicine, New Haven, Connecticut.
| | | | - Jamie Feng
- Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada
| | - Frances Shepherd
- Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada
| | - Elio Adib
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Justin M Cheung
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Jessica J Lin
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Yufei Liu
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Steven H Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | | | | | - Thomas J Dilling
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida
| | - David Kaldas
- Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida; Department of Internal Medicine, University of South Florida, Tampa, Florida; Department of Clinical Oncology, Cairo University, Cairo, Egypt
| | - Jhanelle E Gray
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida
| | - Anastasiya Lobachov
- Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jair Bar
- Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Heike Luders
- Klinik für Pneumologie-Evangelische Lungenklinik Berlin Buch, Berlin, Germany
| | - Christian Grohe
- Klinik für Pneumologie-Evangelische Lungenklinik Berlin Buch, Berlin, Germany
| | - Shruti Gupta
- Department of Hematology and Medical Oncology, Thoracic Medical Oncology Program, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
| | - Ticiana Leal
- Department of Hematology and Medical Oncology, Thoracic Medical Oncology Program, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
| | - Bailey Fitzgerald
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Fionnuala Crowley
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Yu Fujiwara
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Thomas U Marron
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Molly Wilgucki
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Joshua Reuss
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Luxi Chen
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Kamya Sankar
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jacqueline V Aredo
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Joel W Neal
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Heather A Wakelee
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Rohit Thummalapalli
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Helena Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ryan Whitaker
- Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ana Velazquez
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
| | - Meera Ragavan
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Division of Research, Kaiser Permanente Northern California, The Permanente Medical Group, Oakland, California
| | - Alessio Cortellini
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy; Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
| | - David J Kwiatkowski
- Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada
| | | | | | - So Yeon Kim
- Yale University School of Medicine, New Haven, Connecticut
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27
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Atiq MA, Balan J, Blackburn PR, Gross JM, Voss JS, Jin L, Fadra N, Davila JI, Pitel BA, Siqueira Parrilha Terra SB, Minn KT, Jackson RA, Hofich CD, Willkomm KS, Peterson BJ, Clausen SN, Rumilla KM, Gupta S, Lo YC, Ida CM, Molligan JF, Thangaiah JJ, Petersen MJ, Sukov WR, Guo R, Giannini C, Schoolmeester JK, Fritchie K, Inwards CY, Folpe AL, Oliveira AM, Torres-Mora J, Kipp BR, Halling KC. SARCP, a Clinical Next-Generation Sequencing Assay for the Detection of Gene Fusions in Sarcomas: A Description of the First 652 Cases. J Mol Diagn 2025; 27:74-95. [PMID: 39521244 DOI: 10.1016/j.jmoldx.2024.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 10/11/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
An amplicon-based targeted next-generation sequencing (NGS) assay for the detection of gene fusions in sarcomas was developed, validated, and implemented. This assay can detect fusions in targeted regions of 138 genes and BCOR internal tandem duplications. This study reviews our experience with testing on the first 652 patients analyzed. Gene fusions were detected in 238 (36.5%) of 652 cases, including 83 distinct fusions in the 238 fusion-positive cases, 10 of which had not been previously described. Among the 238 fusion-positive cases, the results assisted in establishing a diagnosis for 137 (58%) cases, confirmed a suspected diagnosis in 66 (28%) cases, changed a suspected diagnosis in 25 (10%) cases, and were novel fusions with unknown clinical significance in 10 (4%) cases. Twenty-six cases had gene fusions (ALK, ROS1, NTRK1, NTRK3, and COL1A1::PDGFB) for which there are targetable therapies. BCOR internal tandem duplications were identified in 6 (1.2%) of 485 patients. Among the 138 genes in the panel, 66 were involved in one or more fusions, and 72 were not involved in any fusions. There was little overlap between the genes involved as 5'-partners (31 different genes) and 3'-partners (37 different genes). This study shows the clinical utility of a next-generation sequencing gene fusion detection assay for the diagnosis and treatment of sarcomas.
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Affiliation(s)
- Mazen A Atiq
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jagadheshwar Balan
- Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Patrick R Blackburn
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - John M Gross
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jesse S Voss
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Long Jin
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Numrah Fadra
- Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Jaime I Davila
- Department of Quantitative Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Beth A Pitel
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Kay T Minn
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Rory A Jackson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Christopher D Hofich
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Kurt S Willkomm
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Brenda J Peterson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Sydney N Clausen
- University of Minnesota Medical School, Duluth, Duluth, Minnesota
| | - Kandelaria M Rumilla
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Sounak Gupta
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Ying-Chun Lo
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Cris M Ida
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jeremy F Molligan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Matthew J Petersen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - William R Sukov
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Ruifeng Guo
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Caterina Giannini
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Karen Fritchie
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Carrie Y Inwards
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Andre M Oliveira
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jorge Torres-Mora
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Benjamin R Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
| | - Kevin C Halling
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
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28
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Du Y, Semghouli A, Wang Q, Mei H, Kiss L, Baecker D, Soloshonok VA, Han J. FDA-approved drugs featuring macrocycles or medium-sized rings. Arch Pharm (Weinheim) 2025; 358:e2400890. [PMID: 39865335 PMCID: PMC11771699 DOI: 10.1002/ardp.202400890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 01/28/2025]
Abstract
Macrocycles or medium-sized rings offer diverse functionality and stereochemical complexity in a well-organized ring structure, allowing them to fulfill various biochemical functions, resulting in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular compartments. These features have made macrocycles attractive candidates in organic synthesis and drug discovery. Since the 20th century, more than three-score macrocyclic drugs, including radiopharmaceuticals, have been approved by the US Food and Drug Administration (FDA) for treating bacterial and viral infections, cancer, obesity, immunosuppression, inflammatory, and neurological disorders, managing cardiovascular diseases, diabetes, and more. This review presents 17 FDA-approved macrocyclic drugs during the past 5 years, highlighting their importance and critical role in modern therapeutics, and the innovative synthetic approaches for the construction of these macrocycles.
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Affiliation(s)
- Youlong Du
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
| | - Anas Semghouli
- Institute of Organic Chemistry, Stereochemistry Research Group, HUN‐REN Research Centre for Natural SciencesBudapestHungary
| | - Qian Wang
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
| | - Haibo Mei
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
| | - Loránd Kiss
- Institute of Organic Chemistry, Stereochemistry Research Group, HUN‐REN Research Centre for Natural SciencesBudapestHungary
| | - Daniel Baecker
- Department of Pharmaceutical and Medicinal Chemistry, Institute of PharmacyFreie Universität BerlinBerlinGermany
| | - Vadim A. Soloshonok
- Department of Organic Chemistry I, Faculty of ChemistryUniversity of the Basque Country UPV/EHUSan SebastiánSpain
- IKERBASQUE, Basque Foundation for ScienceBilbaoSpain
| | - Jianlin Han
- Jiangsu Co‐Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical EngineeringNanjing Forestry UniversityNanjingChina
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Athanasiou E, Papageorgiou S, Dafni MF, Kelesis I, Vasileiou M, Tatsiou T, Kouveloglou V, Kanatas P, Stouras I, Gatsis A, Agiassoti VT, Nasimpian P, Dafnoudis D, Degaita K, Verras GI, Alexiou A, Papadakis M, Kamal MA. The use of Isoflavones as Lung Cancer Chemoprevention Agents and their Implications in Treatment through Radio Sensitization. Curr Med Chem 2025; 32:214-237. [PMID: 38369709 DOI: 10.2174/0109298673278897231229121524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/07/2023] [Accepted: 11/21/2023] [Indexed: 02/20/2024]
Abstract
Epidemiological trends in cancer research show that lung cancer can affect up to 1 in 15 men and 1 in 17 women. With incidence rates as high as these and significant associated mortality and morbidity, it is no wonder that lung cancer is one of the main areas of research focused on cancer. Advances in targeted treatments and specialized irradiation protocols have allowed the treatment of more advanced cases. However, as the patient numbers grow, so does the need for cancer-preventive strategies. The present narrative review focuses on soy isoflavones' role in the chemoprevention of lung cancer and their possible role in therapeutic adjuncts. Laboratory studies on lung cancer cell lines have shown that isoflavones can induce apoptosis, tamper with the expression of proliferative molecular pathways, and even reduce tumor angiogenesis. Additionally, population-level studies have emerged that correlate the consumption of isoflavonoids with reduced risk for the development of lung cancer. Interestingly enough, the literature also contains small-scale studies with evidence of isoflavones being effective chemotherapeutic adjuncts that are currently understudied. Our literature review underlines such findings and provides a call for the enhancement of research regarding naturally occurring dietary products with possible anticarcinogenic effects.
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Affiliation(s)
- Efstratios Athanasiou
- Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
| | - Savvas Papageorgiou
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom
| | - Marianna-Foteini Dafni
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Kelesis
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- School of Medicine, Poznań University of Medical Sciences, Poznań, Poland
| | - Maria Vasileiou
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodora Tatsiou
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Biology, University of Crete, Heraklion, Crete, Greece
| | - Vasiliki Kouveloglou
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Panagiotis Kanatas
- Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
| | - Ioannis Stouras
- Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
| | - Athanasios Gatsis
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasiliki-Taxiarchoula Agiassoti
- Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
| | - Petros Nasimpian
- Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
| | - Dimitrios Dafnoudis
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Applied Bioinformatics Master Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kyriaki Degaita
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios-Ioannis Verras
- Cancer Prevention Research Group in Greece, Kifisias Avenue 44, Marousi, Greece
- Department of Surgery, General University Hospital of Patras, Patra, Greece
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
- AFNP Med, Wien, 1030, Austria
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Wuppertal, 42283, Germany
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
- Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia
- Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
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30
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Shimomura Y, Mizutani M, Yoshida H, Ihara Y, Shintani A. Immunotherapy Following Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients with Anaplastic Lymphoma Kinase‑Positive Non‑small Cell Lung Cancer in Japan. Target Oncol 2025; 20:171-180. [PMID: 39607635 DOI: 10.1007/s11523-024-01116-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Although anaplastic lymphoma kinase inhibitors (ALKis) are the effective initial treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), most patients experience resistance to ALKis, leading to the need for alternative therapies. Immune checkpoint inhibitors (ICIs) are a standard NSCLC treatment. On the other hand, their efficacy remains unclear for ALK-positive NSCLC. OBJECTIVE We aim to describe the treatment patterns and treatment outcomes for patients with ALK-positive NSCLC receiving later-line ICI treatment. METHODS This retrospective cohort study used claims data from Japanese acute care hospitals and included patients with lung cancer (International Classification of Diseases, 10th version (ICD-10), code: C34) diagnosed between 1 December 2015 and 31 January 2023. We extracted patients who received ALKis as first-line therapy and subsequent lines of treatment. Patient characteristics and treatment patterns and durations were descriptively summarized. Time to treatment discontinuation (TTD) for ICIs was examined using Kaplan-Meier estimates. RESULTS Of 478 patients who received ALKi as first-line treatment, 30 received ICIs, 249 ALKis, and 154 non-ICI/ALKi therapy as second-line treatment. Most patient characteristics showed no differences among the groups. ICIs were more likely to be administered to patients who underwent shorter durations of ALKi treatment. The median TTD for ICIs was 66 days, with a 1 year TTD rate of 13%. CONCLUSIONS Given the rarity of ALK-positive NSCLC, this study contributes to add evidence through an expanded database and increased sample size, supporting previous suggestions that ICIs have limited effectiveness in patients positive for ALK.
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Affiliation(s)
- Yuki Shimomura
- Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Megumi Mizutani
- Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yasutaka Ihara
- Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
- Data Intelligence Department, Digital Transformation Management Division, Global DX, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Ayumi Shintani
- Department of Medical Statistics, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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31
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Li Q, Cai T, Zheng X, Zhang S, Li C, Tang H, Yu Z, Zhou J. EML4-ALK-Positive Ovarian Cancer With Intracranial Metastasis Responds to Lorlatinib: A Case Report and Literature Review. Clin Case Rep 2025; 13:e70043. [PMID: 39780907 PMCID: PMC11707256 DOI: 10.1002/ccr3.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
We report a case showing that lorlatinib is effective in treating EML4-ALK-positive low-grade serous ovarian cancer (LGSO) with intracranial metastasis. This may be the first clinical evidence of LGSO benefit from ALK inhibitors, to provide evidence for the use of ALK inhibitors in more ovarian cancer patients with EML4-ALK fusion and promoting new ideas for the study of EML4-ALK targets in ovarian cancer.
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Affiliation(s)
- Qiongqian Li
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Tongze Cai
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Xiaoming Zheng
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Shunrong Zhang
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Chanjuan Li
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Huang Tang
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Zhiyong Yu
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
| | - Jianlong Zhou
- Department of OncologyGuangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese MedicineGuangxiChina
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Gardić N, Lovrenski A, Sekeruš V, Kašiković Lečić S, Bijelović M, Lakić T, Ilić A, Zarić B, Glumac S. Cytomorphological and histomorphological features of lung adenocarcinoma with epidermal growth factor receptor mutation and anaplastic lymphoma kinase gene rearrangement. Oncol Lett 2025; 29:40. [PMID: 39530007 PMCID: PMC11552093 DOI: 10.3892/ol.2024.14786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024] Open
Abstract
Lung cancer is among the lethal and most prevalent oncological diseases globally. It is known that two types of mutations, namely anaplastic lymphoma kinase (ALK) gene rearrangement and epidermal growth factor receptor (EGFR) gene mutation, are responsible for the development of lung adenocarcinoma. The present study aimed to investigate the differences in the frequency of clinical, cytomorphological and histomorphological features of ALK and EGFR-positive lung adenocarcinomas. The present retrospective study comprised 101 patients diagnosed with lung adenocarcinoma. Based on the molecular findings, the patients were categorized into three groups as follows: The ALK-rearranged group (n=28), the EGFR group (n=42) and the negative group (n=31). The clinical features analyzed included sex, age, smoking status and disease stage. The cytomorphological and histomorphological features examined encompassed the following: Cell cluster size, the arrangement of tumor cells, the size of nuclei, nuclear atypia, the visibility of nucleoli, the presence of necrosis, intracytoplasmic vacuoles, signet ring cells, stromal characteristics and the presence of inflammatory infiltrate presence. The results indicated that the female sex was more prevalent in the EGFR group, but statistically significant differences (P<0.05) were observed between the EGFR and negative group. A significantly greater percentage of non-smokers was identified in the EGFR group compared with the ALK group (P<0.01). The majority of patients with confirmed ALK or EGFR mutations received onco-specific treatment. Focal and abundant necrosis was significantly less common in cytological samples in the EGFR group than in the other groups (21.43 vs. 57.14 and 51.61%, combined, P<0.01). No significant differences were observed in other cytomorphological features between the groups. Intracytoplasmic vacuoles, signet ring cells and cells with visible nucleoli were significantly more frequent in histological specimens of the ALK group (P<0.01). The predictive model composed of these features or combined with sex and smoking habits exhibited statistically significant differences for mutation status as a criterion (P<0.01). Collectively, the findings of the present study confirmed that, in addition to clinical characteristics, certain cytological and histological features of lung adenocarcinoma are associated with the mutational status of the tumor.
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Affiliation(s)
- Nikola Gardić
- Department of Pathology, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
- Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica 21204, Serbia
| | - Aleksandra Lovrenski
- Department of Pathology, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
- Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica 21204, Serbia
| | - Vanesa Sekeruš
- Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica 21204, Serbia
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
| | - Svetlana Kašiković Lečić
- Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica 21204, Serbia
- Department of Internal Medicine, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
| | - Milorad Bijelović
- Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica 21204, Serbia
- Department of Surgery, Faculty of Medicine Foca, University of East Sarajevo, Foča 73300, Bosnia and Herzegovina
| | - Tanja Lakić
- Department of Pathology, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
- Center of Pathology and Histology, University Clinical Center of Vojvodina, Novi Sad 21000, Serbia
| | - Aleksandra Ilić
- Department of Pathology, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
- Center of Pathology and Histology, University Clinical Center of Vojvodina, Novi Sad 21000, Serbia
| | - Bojan Zarić
- Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica 21204, Serbia
- Department of Internal Medicine, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
| | - Sofija Glumac
- Institute of Pathology, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia
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Bearz A, Bertoli E, Stanzione B, De Carlo E, Del Conte A, Bortolot M, Torresan S, Berto E, Da Ros V, Pelin GM, Fassetta K, Rossetto S, Spina M. EML4-ALK: Update on ALK Inhibitors. Int J Mol Sci 2025; 26:308. [PMID: 39796163 PMCID: PMC11719670 DOI: 10.3390/ijms26010308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/29/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation. This review traces the main milestones in the treatment of ALK-positive metastatic patients and the survival outcomes in the first-line and second-line settings with different ALK inhibitors. It presents the two options available for first-line treatment at the present time: sequencing different ALK inhibitors versus using the most potent inhibitor in front-line treatment. The efficacy outcomes of different ALK inhibitors in the first-line setting; the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations; and patients' co-morbidities and inhibitor toxicities should be taken into account to address the choice of the first-line treatment, as suggested in this review.
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Affiliation(s)
- Alessandra Bearz
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Elisa Bertoli
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Brigida Stanzione
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Elisa De Carlo
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Alessandro Del Conte
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Martina Bortolot
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Sara Torresan
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Eleonora Berto
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Valentina Da Ros
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Giulia Maria Pelin
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Kelly Fassetta
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
| | - Silvia Rossetto
- Centro di Riferimento Oncologico di Aviano (CRO), National Cancer Institute, IRCCS, 33081 Aviano, Italy; (E.B.); (A.D.C.); (G.M.P.); (S.R.)
| | - Michele Spina
- Centro di Riferimento Oncologico di Aviano (CRO), Department of Medical Oncology, IRCCS, 33081 Aviano, Italy; (B.S.); (E.D.C.); (E.B.); (V.D.R.); (K.F.); (M.S.)
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Chayab L, Leighl NB, Tadrous M, Warren CM, Wong WWL. Trends in Real-World Clinical Outcomes of Patients with Anaplastic Lymphoma Kinase (ALK) Rearranged Non-Small Cell Lung Cancer (NSCLC) Receiving One or More ALK Tyrosine Kinase Inhibitors (TKIs): A Cohort Study in Ontario, Canada. Curr Oncol 2024; 32:13. [PMID: 39851929 PMCID: PMC11764221 DOI: 10.3390/curroncol32010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/21/2024] [Accepted: 12/24/2024] [Indexed: 01/30/2025] Open
Abstract
The treatment landscape for patients with advanced ALK-positive NSCLC has rapidly evolved following the approval of several ALK TKIs in Canada. However, public funding of ALK TKIs is mostly limited to the first line treatment setting. Using linked provincial health administrative databases, we examined real-world outcomes of patients with advanced ALK-positive NSCLC receiving ALK TKIs in Ontario between 1 January 2012 and 31 December 2021. Demographic, clinical characteristics and treatment patterns were summarized using descriptive statistics. Kaplan-Meier analysis was performed to evaluate progression-free survival (PFS) and overall survival (OS) among the treatment groups. A total of 413 patients were identified. Patients were administered alectinib (n = 154), crizotinib (n = 80), or palliative-intent chemotherapy (n = 55) in the first-line treatment. There was a significant difference in first-line PFS between the treatment groups. The median PFS (mPFS) was not reached for alectinib (95% CI, 568 days-not reached), compared to 8.2 months (95% CI, 171-294 days) for crizotinib (HR = 0.34, p < 0.0001) and 2.4 months (95% CI, 65-100 days) for chemotherapy (HR = 0.14, p < 0.0001). There was no significant difference in first-line OS between the treatment groups. In patients who received more than one line of treatment, there was a significant difference in mOS between patients who received two or more lines of ALK TKIs compared to those who received one line of ALK TKI (mOS = 55 months (95% CI, 400-987 days) and 26 months (95% CI, 1448-2644 days), respectively, HR = 4.64, p < 0.0001). This study confirms the effectiveness of ALK TKIs in real-world practice and supports the potential benefit of multiple lines of ALK TKI on overall survival in patients with ALK-positive NSCLC.
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Affiliation(s)
- Lara Chayab
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada;
| | - Natasha B. Leighl
- Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada;
- Department of Medicine, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Mina Tadrous
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada;
- Women’s College Research Institute, Toronto, ON M5G 1N8, Canada
| | | | - William W. L. Wong
- School of Pharmacy, University of Waterloo, Waterloo, ON N2L 3G1, Canada;
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35
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Sampson J, Ju HM, Zhang N, Yeoh S, Choi J, Bayliss R. Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer. Cell Death Dis 2024; 15:912. [PMID: 39695132 DOI: 10.1038/s41419-024-07272-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 11/22/2024] [Accepted: 11/29/2024] [Indexed: 12/20/2024]
Abstract
The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/metabolism
- Receptor, ErbB-3/metabolism
- Receptor, ErbB-3/genetics
- Oncogene Proteins, Fusion/metabolism
- Oncogene Proteins, Fusion/genetics
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lung Neoplasms/drug therapy
- Lung Neoplasms/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Cell Line, Tumor
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Lactams/pharmacology
- Protein Kinase Inhibitors/pharmacology
- Aminopyridines/pharmacology
- Signal Transduction/drug effects
- Pyrazoles/pharmacology
- Neuregulin-1/metabolism
- Neuregulin-1/genetics
- Lactams, Macrocyclic/pharmacology
- Anaplastic Lymphoma Kinase/genetics
- Anaplastic Lymphoma Kinase/metabolism
- Anaplastic Lymphoma Kinase/antagonists & inhibitors
- Apoptosis/drug effects
- ErbB Receptors/metabolism
- ErbB Receptors/genetics
- ErbB Receptors/antagonists & inhibitors
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Affiliation(s)
- Josephina Sampson
- Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
| | - Hyun-Min Ju
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Korea
| | - Nan Zhang
- Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
| | - Sharon Yeoh
- Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
| | - Jene Choi
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Korea.
| | - Richard Bayliss
- Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
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Yang CY, Liao WY, Ho CC, Chen KY, Tsai TH, Hsu CL, Su KY, Chang YL, Wu CT, Hsu CC, Liu YN, Peng GR, Kangartaputra AA, Yu SH, Liao BC, Hsu WH, Lee JH, Lin CC, Shih JY, Chih-Hsin Yang J, Yu CJ. PD-L1 expression and immune profiling cannot predict osimertinib efficacy in lung cancer with EGFR T790 M mutation: A translational study. J Formos Med Assoc 2024:S0929-6646(24)00579-5. [PMID: 39694766 DOI: 10.1016/j.jfma.2024.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 10/10/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND PD-L1 is associated with poor efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in untreated EGFR-mutant non-small-cell lung cancer (NSCLC). Whether PD-L1 is also predictive of osimertinib efficacy in pre-treated patients with an acquired EGFR T790 M mutation is unclear. PATIENTS AND METHODS PD-L1 expression and tumor microenvironments were evaluated in tumors from EGFR-mutant T790 M + NSCLC patients treated with osimertinib. In vitro and in vivo experiments were also performed to examine the effect of PD-L1 overexpression on osimertinib susceptibility in EGFR T790 M + cells. RESULTS A total of 134 pre-treated EGFR T790 M + patients were enrolled, of whom 72 had del19, 58 had L858R, and 4 had G719X as initial EGFR mutation subtype. Positive PD-L1 expression (TC ≥ 1%) was found in 21 of 134 (15.7%) patients. PD-L1 expression did not differ across different biopsied sites and among different EGFR mutation subgroups. Kaplan-Meier estimate revealed no significant difference in progression-free survival (PFS) in PD-L1-positive versus PD-L1-negative patients. Multivariate analysis using the Cox proportional hazard model found that older age and L858R mutation were independent predictive factors. Multiplex IHC showed that immune cell infiltration was not associated with PD-L1 expression or osimertinib treatment response. By overexpressing PD-L1 in EGFR T790 M + cells, we found that PD-L1 did not result in osimertinib resistance in in vitro and xenograft models. CONCLUSIONS PD-L1 expression in pre-treated EGFR T790 M + lung adenocarcinoma is not predictive of osimertinib efficacy, as demonstrated by in vitro, xenograft, and clinical case studies.
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Affiliation(s)
- Ching-Yao Yang
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wei-Yu Liao
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chao-Chi Ho
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuan-Yu Chen
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tzu-Hsiu Tsai
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Lin Hsu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kang-Yi Su
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yih-Leong Chang
- Department of Pathology, National Taiwan University Hospital, National Taiwan University Cancer Center, and National Taiwan University College of Medicine, Taipei, Taiwan.
| | - Chen-Tu Wu
- Department of Pathology, National Taiwan University Hospital, National Taiwan University Cancer Center, and National Taiwan University College of Medicine, Taipei, Taiwan.
| | - Chia-Chi Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Nan Liu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Guan-Ru Peng
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
| | | | - Shu-Han Yu
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan
| | - Bin-Chi Liao
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Hsun Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jih-Hsiang Lee
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Chi Lin
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jin-Yuan Shih
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - James Chih-Hsin Yang
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
| | - Chong-Jen Yu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Huang L, Kong W, Luo Y, Xie H, Liu J, Zhang X, Zhang G. Predicting epidermal growth factor receptor mutation status of lung adenocarcinoma based on PET/CT images using deep learning. Front Oncol 2024; 14:1458374. [PMID: 39735601 PMCID: PMC11671303 DOI: 10.3389/fonc.2024.1458374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/20/2024] [Indexed: 12/31/2024] Open
Abstract
Background The aim of this study is to develop deep learning models based on 18F-fluorodeoxyglucose positron emission tomography/computed tomographic (18F-FDG PET/CT) images for predicting individual epidermal growth factor receptor (EGFR) mutation status in lung adenocarcinoma (LUAD). Methods We enrolled 430 patients with non-small-cell lung cancer from two institutions in this study. The advanced Inception V3 model to predict EGFR mutations based on PET/CT images and developed CT, PET, and PET + CT models was used. Additionally, each patient's clinical characteristics (age, sex, and smoking history) and 18 CT features were recorded and analyzed. Univariate and multivariate regression analyses identified the independent risk factors for EGFR mutations, and a clinical model was established. The performance using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, recall, and F1-value was evaluated. The DeLong test was used to compare the predictive performance across various models. Results Among these four models, deep learning models based on CT and PET + CT exhibit the same predictive performance, followed by PET and the clinical model. The AUC values for CT, PET, PET + CT, and clinical models in the training set are 0.933 (95% CI, 0.922-0.943), 0.895 (95% CI, 0.882-0.907), 0.931 (95% CI, 0.921-0.942), and 0.740 (95% CI, 0.685-0.796), respectively; whereas those in the testing set are:0.921 (95% CI, 0.904-0.938), 0.876 (95% CI, 0.855-0.897), 0.921 (95% CI, 0.904-0.937), and 0.721 (95% CI, 0.629-0.814), respectively. The DeLong test results confirm that all deep learning models are superior to clinical one. Conclusion The PET/CT images based on trained CNNs effectively predict EGFR and non-EGFR mutations in LUAD. The deep learning predictive models could guide treatment options.
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Affiliation(s)
- Lele Huang
- Department of Nuclear Medicine, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Weifang Kong
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yongjun Luo
- Department of Nuclear Medicine, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Hongjun Xie
- Department of Nuclear Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jiangyan Liu
- Department of Nuclear Medicine, The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China
- Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China
- Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Xin Zhang
- Department of Pharmaceuticals Diagnosis, GE Healthcare, Beijing, China
| | - Guojin Zhang
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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38
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Wu Q, Nandi D, Sharma D. TRIM-endous functional network of tripartite motif 29 (TRIM29) in cancer progression and beyond. Cancer Metastasis Rev 2024; 44:16. [PMID: 39644332 PMCID: PMC11625080 DOI: 10.1007/s10555-024-10226-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 10/16/2024] [Indexed: 12/09/2024]
Abstract
While most Tripartite motif (TRIM) family proteins are E3 ubiquitin ligases, some members have functions beyond the regulation of ubiquitination, impacting normal physiological processes and disease progression. TRIM29, an important member of the TRIM family, exerts a predominant influence on cancer growth, epithelial-to-mesenchymal transition, stemness and metastatic progression by directly potentiating multiple canonical oncogenic pathways. The cancer-promoting effect of TRIM29 is also evident in metabolic interventions and interference with the efficacy of cancer therapeutics. As expected for any key node in cancer, the expression of TRIM29 is tightly regulated by non-coding RNAs, epigenetic modulation, and post-translational regulation. A systematic discussion of how TRIM29 is regulated in cancer, its influences on cancer progression, and its impact on cancer therapeutics is presented in this review. We also explore the context-dependent alterations between TRIM29 function from oncogenic to tumor suppression. As TRIM29 is involved in multiple aspects of cancer progression, a better understanding of its biological impact in cancer may help improve prognosis and develop novel therapeutic combinations, leading to improved personalized cancer care.
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Affiliation(s)
- Qitong Wu
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Deeptashree Nandi
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Dipali Sharma
- Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD, 21231, USA.
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39
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Zhou H, Hu M, Jie H, Li Y, Tang K, Pan L, Liu C, Liu Z, Chen W, Chen Y, Luo Y, Gong Y, Xie Y. Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers. Eur J Med Chem 2024; 279:116827. [PMID: 39288596 DOI: 10.1016/j.ejmech.2024.116827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 08/30/2024] [Accepted: 08/31/2024] [Indexed: 09/19/2024]
Abstract
Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC50 = 119.33 nM, Dmax = 97.1 %) and showed comparable anti-proliferative activity to Ceritinib (IC50 = 3.11 ± 0.08 nM vs IC50 = 1.31 ± 0.43 nM). Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC50 = 52.82 nM vs IC50 = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies.
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Affiliation(s)
- Haoxuan Zhou
- Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mingxing Hu
- Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hui Jie
- Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yujue Li
- Department of Nuclear Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Kexin Tang
- Department of Biology, Emory University, Atlanta, 30322, USA
| | - LiLi Pan
- Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chengyali Liu
- Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zi Liu
- Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wei Chen
- Department of Nuclear Medicine and Clinical Nuclear Medicine Research Lab, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuanwei Chen
- Hinova Pharmaceuticals Inc., Chengdu, 610041, China
| | - Yi Luo
- Department of Orthopedics and Orthopaedic Research Institute, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Youling Gong
- Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Yongmei Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
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40
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Chen P, Zheng X, Li C, Li J, Yang C, Feng Y, Cheng B, Liang H, Liu Z, Zhao Y, Xiong S, Li F, Zhong R, Zhan S, Wang H, Xiang Y, Fu W, Ye W, Jiang B, Fan X, Liu J, He J, Liang W. Association of pre-existing conditions with major driver mutations and PD-L1 expression in NSCLC. BMJ Open Respir Res 2024; 11:e002571. [PMID: 39632102 PMCID: PMC11624786 DOI: 10.1136/bmjresp-2024-002571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/24/2024] [Indexed: 12/07/2024] Open
Abstract
OBJECTIVES This study aims to explore how pre-existing conditions such as blood types, family history of cancer and comorbid diseases correlate with the genetic and programmed death-ligand 1 (PD-L1) expression that contributes to the heterogeneous biological behaviours of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS A cohort of 5507 NSCLC patients who underwent surgical resection between January 2014 and July 2018 was studied. Targeted next-generation sequencing was used to detect mutations in nine pivotal cancer-related genes, and immunohistochemical staining was applied to assess PD-L1 expression. Logistic regression analysis was employed to identify significant correlations. RESULTS All patients underwent NGS, with 1839 were also evaluated for PD-L1 expression. Several significant findings were found: ROS1 mutations were closely associated with a family history of lung cancer (OR 7.499, 95% CI 1.094 to 30.940, p=0.013). Epidermal growth factor receptor (EGFR) L858R mutations were common among patients with a family history of non-lung cancers and those with hypertension (OR 2.089, 95% CI 1.029 to 4.135, p=0.037 and OR 1.252, 95% CI 1.001 to 1.562, p=0.048, respectively). Pre-existing conditions such as diabetes and hepatitis B surface antigen positivity (OR 1.468, 95% CI 1.042 to 2.047, p=0.026 and OR 1.373, 95% CI 1.012 to 1.847, p=0.038, respectively) were correlated with EGFR exon 19 deletions. RhD negativity showed potential ties to BRAF mutations (OR 0.010, 95% CI 0.001 to 0.252, p=0.001). A history of tuberculosis linked to increased PD-L1 expression in immune cells (OR 3.597, 95% CI 1.295 to 14.957, p=0.034). CONCLUSION This large-scale, cross-sectional study reveals a complex interplay between genetic mutations, immunological features and pre-existing conditions in NSCLC patients, offering insights that could inform personalised treatment strategies.
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Affiliation(s)
- Peiling Chen
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Xin Zheng
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Caichen Li
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Jianfu Li
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Chen Yang
- Department of Mathematical Sciences, University of Southampton, Southampton, UK
| | - Yi Feng
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Bo Cheng
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Hengrui Liang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Zhichao Liu
- Department of Thoracic Surgery, Shanghai Institute of Thoracic Oncology, Shanghai, China
| | - Yi Zhao
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Shan Xiong
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Feng Li
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Ran Zhong
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Shuting Zhan
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Huiting Wang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Yang Xiang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Wenhai Fu
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Wenjun Ye
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Bo’ao Jiang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Xianzhe Fan
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Jun Liu
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Jianxing He
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
| | - Wenhua Liang
- Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou, Guangdong, China
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41
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Podder V, Ranjan T, Gowda M, Camacho AM, Ahluwalia MS. Emerging Therapies for Brain Metastases in NSCLC, Breast Cancer, and Melanoma: A Critical Review. Curr Neurol Neurosci Rep 2024; 25:6. [PMID: 39625633 DOI: 10.1007/s11910-024-01388-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2024] [Indexed: 12/17/2024]
Abstract
PURPOSE OF REVIEW Advancements in precision medicine have shifted the treatment paradigm of brain metastases (BM) from non-small cell lung cancer (NSCLC), breast cancer, and melanoma, especially through targeted therapies focused on specific molecular drivers. These novel agents have improved outcomes by overcoming challenges posed by the blood-brain barrier (BBB) and resistance mechanisms, enabling more effective treatment of BM. RECENT FINDINGS In NSCLC, therapies such as osimertinib have improved efficacy in treating EGFR-mutant BM, with emerging combinations such as amivantamab and lazertinib offering promising alternatives for patients resistant to frontline therapies. In HER2-positive breast cancer, significant advancements with tucatinib and trastuzumab deruxtecan (T-DXd) have transformed the treatment landscape, achieving improved survival and intracranial control in patients with BM. Similarly, in triple-negative breast cancer (TNBC), novel therapies such as sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) offer new hope for managing BM. For melanoma, the combination of immune checkpoint inhibitors such as nivolumab and ipilimumab has proven effective in enhancing survival for patients with BM, both in BRAF-mutant and wild-type cases. Developing targeted therapies penetrating the BBB has revolutionized BM treatment by targeting key drivers like EGFR, ALK, HER2, and BRAF. Despite improved survival, challenges persist, particularly for patients with resistant genetic alterations. Future research should optimise combination therapies, overcome resistance, and refine treatment sequencing. Continued emphasis on personalized, biomarker-driven approaches offers the potential to further improve outcomes, even for complex cases.
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Affiliation(s)
- Vivek Podder
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Tulika Ranjan
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
| | - Maya Gowda
- Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
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42
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Lin JJ, Horan JC, Tangpeerachaikul A, Swalduz A, Valdivia A, Johnson ML, Besse B, Camidge DR, Fujino T, Yoda S, Nguyen-Phuong L, Mizuta H, Bigot L, Nobre C, Lee JB, Yu MR, Mente S, Sun Y, Kohl NE, Porter JR, Shair MD, Zhu VW, Felip E, Cho BC, Friboulet L, Hata AN, Pelish HE, Drilon A. NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations. Cancer Discov 2024; 14:2367-2386. [PMID: 39269178 PMCID: PMC11609626 DOI: 10.1158/2159-8290.cd-24-0231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 05/25/2024] [Accepted: 08/06/2024] [Indexed: 09/15/2024]
Abstract
Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.
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Affiliation(s)
- Jessica J. Lin
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | | | | | | | - Augusto Valdivia
- Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain
| | | | - Benjamin Besse
- Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif, France
| | - D. Ross Camidge
- University of Colorado, Anschutz Medical Campus, Aurora, Colorado
| | - Toshio Fujino
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Satoshi Yoda
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | | | - Hayato Mizuta
- Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif, France
| | - Ludovic Bigot
- Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif, France
| | - Catline Nobre
- Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif, France
| | - Jii Bum Lee
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Mi Ra Yu
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Scot Mente
- Nuvalent, Inc., Cambridge, Massachusetts
| | - Yuting Sun
- Nuvalent, Inc., Cambridge, Massachusetts
| | | | | | | | | | - Enriqueta Felip
- Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain
| | - Byoung Chul Cho
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Luc Friboulet
- Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif, France
| | - Aaron N. Hata
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | | | - Alexander Drilon
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
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43
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Du M, Liu C, Chen L, Li Z, Zhang S, Meng R. Concomitant ALK Fusion and TP53/EGFR Mutation Lead to Adverse Prognostic Outcome. THE CLINICAL RESPIRATORY JOURNAL 2024; 18:e70041. [PMID: 39681089 DOI: 10.1111/crj.70041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 11/11/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024]
Abstract
Lung cancer treatment has evolved at the molecular level. Detecting the presence of driver genes in lung cancer fundamentally alters the choice of therapeutic regimens and the outcome of this disease. ALK fusion mutation is one of the most important mutations in nonsmall cell lung cancer (NSCLC). Also, it often has other coexisting mutation types. TP53 is the most common coexisting mutation type, whereas the EGFR/ALK coexisting mutation type is extremely rare. There is still no definite conclusion about the impact of the multimutation and best treatment options for NSCLC patients with advanced multimutation. In this study, we report three cases of NSCLC with ALK fusion mutations as well as ALK combined with TP53 mutations and ALK combined with EGFR mutations. Combining cases from our oncology center and previous literature, we found that NSCLC patients with coexisting ALK fusion mutations and other mutations have poorer response to targeted therapy and poorer prognosis, and we also compared the efficacy rates of various types of coexisting mutations for different treatment regimens. Therefore, this review can help to evaluate the prognosis of NSCLC patients with coexisting mutations and the efficacy of targeted therapies and to find more favorable treatment options for patients with this type of coexisting mutations.
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Affiliation(s)
- Mingyuan Du
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Leichong Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenyu Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sijia Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Meng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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44
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Nobuoka M, Mukawa T, Iwaya M, Shigeto S, Minagawa T, Uehara T, Akiyama Y. SMARCB1-deficient renal medullary carcinoma with an EML4::ALK fusion gene in a Japanese woman. Pathol Int 2024; 74:704-707. [PMID: 39503184 DOI: 10.1111/pin.13494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 12/13/2024]
Abstract
Renal medullary carcinoma is a rare, high-grade carcinoma arising in the renal medulla, which is usually associated with sickle cell trait, and there are very few documented cases in the Japanese population. We report a case of renal medullary carcinoma, immunohistochemically defined as SMARCB1 deficient, in a 67-year-old Japanese woman without a history of sickle cell trait. Somatic mutation of SMARCB1 and an EML4::ALK fusion gene were identified by comprehensive genomic profiling. Computed tomography revealed metastatic lesions in the retrocaval lymph nodes, liver, and bronchus. Six cycles of the dose-dense methotrexate, vinblastine, adriamycin, and cisplatin-combined chemotherapy were completed after an ultrasound-guided percutaneous biopsy of the renal tumor. After chemotherapy, the size of the original tumor in the right kidney had decreased in size, as well as the other metastatic lesions.
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Affiliation(s)
- Megumi Nobuoka
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Tatsuya Mukawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Shohei Shigeto
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Tomonori Minagawa
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yoshiyuki Akiyama
- Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan
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45
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Wang KL, Yeh TY, Hsu PC, Wong TH, Liu JR, Chern JW, Lin MH, Yu CW. Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer. J Enzyme Inhib Med Chem 2024; 39:2318645. [PMID: 38465731 DOI: 10.1080/14756366.2024.2318645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 01/11/2024] [Indexed: 03/12/2024] Open
Abstract
A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.
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Affiliation(s)
- Kang-Li Wang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tsung-Yu Yeh
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Chen Hsu
- Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tzu-Hsuan Wong
- Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jia-Rong Liu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ji-Wang Chern
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Miao-Hsia Lin
- Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chao-Wu Yu
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
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46
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Zhang X, Tong J, Wang T, Wang Z, Gu S, Xu L, Hou T, Pan P. In-depth theoretical modeling to explore the mechanism of TPX-0131 overcoming lorlatinib resistance to ALK L1196M/G1202R mutation. Comput Biol Med 2024; 183:109265. [PMID: 39405725 DOI: 10.1016/j.compbiomed.2024.109265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/19/2024] [Accepted: 10/07/2024] [Indexed: 11/20/2024]
Abstract
A number of anaplastic lymphoma kinase (ALK) inhibitors have been clinically approved, with lorlatinib, particularly as a third-generation drug, demonstrating efficacy against various drug-resistant ALK single mutations. However, continued clinical use of lorlatinib has led to the emergence of ALK double mutations conferring resistance to lorlatinib, notably ALKL1196M/G1202R. TPX-0131 is a potential fourth-generation ALK inhibitor currently under development. TPX-0131 demonstrates a broader spectrum of activity against ALK-resistant mutations, efficiently inhibiting 26 single-point mutations and various double/triple mutations, including solvent front mutations and gatekeeper mutations. In this study, for the first time, a comprehensive elucidation of the molecular mechanisms by which TPX-0131 overcomes lorlatinib resistance to ALKL1196M/G1202R through modeling, MD simulations, free energy calculations, and US simulations. The results indicate that the interactions between lorlatinib and key residues at the hinge region are disturbed by L1196M/G1202R double mutation, leading to the disruption of important hydrogen bonding between Glu1197 and lorlatinib. For TPX-0131, the L1196M/G1202R mutation enhances electrostatic and van der Waals interactions, causing significant conformational changes primarily in the hinge region, G-loop, and β-strands. The tight binding of TPX-0131 to residues Arg1202, Met1199 and Arg1120 contribute significantly to overcoming lorlatinib resistance in ALKL1196M/G1202R mutant. These research results are expected to offer insights into the mechanism of TPX-0131 in treating ALKG1202R/L1196M-induced NSCLC resistance and optimizing of ALK inhibitors.
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Affiliation(s)
- Xing Zhang
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China
| | - Jianbo Tong
- College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China.
| | - Tianhao Wang
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China; College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an, 710021, PR China
| | - Zhe Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 310058, Zhejiang, PR China
| | - Shukai Gu
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China
| | - Lei Xu
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, PR China
| | - Tingjun Hou
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China.
| | - Peichen Pan
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, PR China.
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47
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Mizuno Y, Tada Y, Uehara T, Yamashita S, Murai H. A Case of Small-Cell Lung Cancer With Novel Anaplastic Lymphoma Kinase Gene Rearrangement That Developed Intradural Extramedullary Spinal Metastases With Myelitis. Cureus 2024; 16:e75369. [PMID: 39781173 PMCID: PMC11707969 DOI: 10.7759/cureus.75369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2024] [Indexed: 01/12/2025] Open
Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangement-positive small-cell lung cancer (SCLC) is extremely rare. A 73-year-old man was diagnosed with SCLC. Standard treatments were not effective. Furthermore, at 74 years of age, intradural extramedullary metastases in the lumbar spinal cord and myelitis were observed. Autoimmune myelitis was suspected because anti-Zic4 antibodies were detected. However, steroid pulse therapy was ineffective. Interestingly, a novel ALK rearrangement of the isoamyl acetate hydrolyzing esterase 1 (IAH1)-ALK fusion gene was identified by blood-based next-generation sequencing. Although it was unclear whether the IAH1-ALK fusion gene was involved in tumor progression or an asymptomatic mutation, we treated the patient with alectinib, an ALK inhibitor; however, this therapy did not reduce the lesions. There is no established effective treatment for patients with SCLC who are ALK fusion gene positive by liquid biopsy. Therefore, patient-specific approaches and treatments are required.
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Affiliation(s)
- Yuri Mizuno
- Department of Neurology, International University of Health and Welfare Narita Hospital, Narita, JPN
| | - Yuji Tada
- Department of Respirology, International University of Health and Welfare Narita Hospital, Narita, JPN
| | - Taira Uehara
- Epilepsy and Sleep Center, Fukuoka Sanno Hospital, Fukuoka, JPN
- Department of Neurology, International University of Health and Welfare Narita Hospital, Narita, JPN
| | - Satoshi Yamashita
- Department of Neurology, International University of Health and Welfare Narita Hospital, Narita, JPN
| | - Hiroyuki Murai
- Department of Neurology, International University of Health and Welfare Narita Hospital, Narita, JPN
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48
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Bae K, Kim DE, Kim JH, Lee JY, Yoon KA. Oncogenic fusion of CD63-BCAR4 contributes cancer stem cell-like properties via ALDH1 activity. Mol Carcinog 2024; 63:2282-2290. [PMID: 39136580 DOI: 10.1002/mc.23808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 06/13/2024] [Accepted: 07/30/2024] [Indexed: 11/16/2024]
Abstract
Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.
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Affiliation(s)
- Kieun Bae
- College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Dong Eon Kim
- College of Health Science, Cheongju University, Cheongju, Republic of Korea
| | - Jin Hee Kim
- College of Health Science, Cheongju University, Cheongju, Republic of Korea
| | - Ja Young Lee
- College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
| | - Kyong-Ah Yoon
- College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
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49
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Park SM, Haam K, Heo H, Kim D, Kim MJ, Jung HJ, Cha S, Kim M, Lee H. Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer. Mol Oncol 2024. [PMID: 39540457 DOI: 10.1002/1878-0261.13738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 08/02/2024] [Accepted: 09/10/2024] [Indexed: 11/16/2024] Open
Abstract
Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.
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Affiliation(s)
- Sang-Min Park
- College of Pharmacy, Chungnam National University, Daejeon, Korea
| | - Keeok Haam
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Haejeong Heo
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon, Korea
| | - Doyeong Kim
- College of Pharmacy, Chungnam National University, Daejeon, Korea
| | - Min-Ju Kim
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Korea
| | - Hyo-Jung Jung
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Seongwon Cha
- Korean Medicine (KM) Data Division, Korea Institute of Oriental Medicine, Daejeon, Korea
| | - Mirang Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon, Korea
| | - Haeseung Lee
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Korea
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50
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Qu D, Yan A. Classification models and SAR analysis of anaplastic lymphoma kinase (ALK) inhibitors using machine learning algorithms with two data division methods. Mol Divers 2024:10.1007/s11030-024-10990-x. [PMID: 39531134 DOI: 10.1007/s11030-024-10990-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 09/06/2024] [Indexed: 11/16/2024]
Abstract
Anaplastic lymphoma kinase (ALK) plays a critical role in the development of various cancers. In this study, the dataset of 1810 collected inhibitors were divided into a training set and a test set by the self-organizing map (SOM) and random method, respectively. We developed 32 classification models using Support Vector Machines (SVM), Decision Trees (DT), Random Forests (RF), and Extreme Gradient Boosting (XGBoost) to distinguish between highly and weakly active ALK inhibitors, with the inhibitors represented by MACCS and ECFP4 fingerprints. Model 7D which was built by the RF algorithm using training set 1/test set 1 divided by the SOM method, provided the best performance with a prediction accuracy of 90.97% and a Matthews correlation coefficient (MCC) value of 0.79 on the test set. We clustered the 1810 inhibitors into 10 subsets by K-Means algorithm to find out the structural characteristics of highly active ALK inhibitors. The main scaffolds of highly active ALK inhibitors were also analyzed based on ECFP4 fingerprints. It was found that some substructures have a significant effect on high activity, such as 2,4-diarylaminopyrimidine analogues, pyrrolo[2,1-f][1,2,4]triazin, indolo[2,3-b]quinoline-11-one, benzo[d]imidazol and pyrrolo[2,3-b]pyridine. In addition, the subsets were summarized into several clusters, among which four clusters showed a significant relationship with ALK inhibitory activity. Finally, Shapley additive explanations (SHAP) was also used to explain the influence of modeling features on model prediction results. The SHAP results indicated that our models can well reflect the structural features of ALK inhibitors.
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Affiliation(s)
- Dan Qu
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, 15 BeiSanHuan East Road, P.O. Box 53, Beijing, 100029, People's Republic of China
| | - Aixia Yan
- State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, 15 BeiSanHuan East Road, P.O. Box 53, Beijing, 100029, People's Republic of China.
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