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Zou Y, Wan X, Zhou Q, Zhu G, Lin S, Tang Q, Yang X, Wang S. Mechanisms of drug resistance in hepatocellular carcinoma. Biol Proced Online 2025; 27:19. [PMID: 40437363 PMCID: PMC12117952 DOI: 10.1186/s12575-025-00281-6] [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: 01/22/2025] [Accepted: 05/12/2025] [Indexed: 06/01/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, associated with high morbidity and mortality worldwide. Despite advancements in diagnostic methods and systemic treatments, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), the development of drug resistance remains a significant challenge in HCC management. Traditional treatments such as surgical resection and transarterial chemoembolization offer limited efficacy, especially in advanced stages. Although novel therapies like lenvatinib, sorafenib, regorafenib, and ICIs have shown promise, their effectiveness is often hindered by primary and acquired resistance, leading to poor long-term survival outcomes. This review focuses on the molecular mechanisms underlying resistance to targeted therapies and immunotherapies in HCC. Key factors contributing to resistance include alterations in the tumor microenvironment (TME), immune evasion, hypoxia, changes in cellular metabolism, and genetic mutations. Additionally, molecular players such as ferroptosis, autophagy, apoptosis, endoplasmic reticulum stress, ABC transporters, and non-coding RNAs(ncRNAs) are discussed as contributors to drug resistance. Understanding these mechanisms is critical for the development of novel therapeutic strategies aimed at overcoming resistance, improving patient outcomes, and ultimately enhancing survival rates in HCC patients.
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Affiliation(s)
- Yongchun Zou
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Xinliang Wan
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Qichun Zhou
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Gangxing Zhu
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Shanshan Lin
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China
| | - Qing Tang
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
| | - Xiaobing Yang
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
| | - Sumei Wang
- Clinical and Basic Research Team of TCM Prevention and Treatment of NSCLC, Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Chinese Medicine Guangdong Laboratory, State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou, Guangdong, 510120, China.
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Suzuki K, Inoue K, Namiguchi R, Morita S, Hayakawa S, Yokota M, Sakai K, Matsumoto K, Aoki S. Identification of Novel Compounds That Bind to the HGF β-Chain In Silico, Verification by Molecular Mechanics and Quantum Mechanics, and Validation of Their HGF Inhibitory Activity In Vitro. Molecules 2025; 30:1801. [PMID: 40333783 PMCID: PMC12029800 DOI: 10.3390/molecules30081801] [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: 02/18/2025] [Revised: 04/06/2025] [Accepted: 04/12/2025] [Indexed: 05/09/2025] Open
Abstract
The development of small-molecule drugs targeting growth factors for cancer therapy remains a significant challenge, with only limited successful cases. We attempted to identify hepatocyte growth factor (HGF) inhibitors as novel anti-cancer small-molecule drugs. To identify compounds that bind to the β-chain of HGF and inhibit signaling through HGF and its receptor Met interaction, we performed a hierarchical in silico drug screen using a three-dimensional compound structure library (Chembridge, 154,118 compounds). We experimentally tested whether 10 compounds selected as candidates for novel anticancer agents exhibit inhibition of HGF activity. Compounds 6 and 7 potently inhibited Met phosphorylation in the human EHEMES-1 cell line, with IC50 values of 20.4 and 11.9 μM, respectively. Molecular dynamics simulations of the Compound 6/7-HGF β-chain complex structures suggest that Compounds 6 and 7 stably bind to the interface pocket of the HGF β-chain. MM-PBSA, MM-GBSA, and FMO analyses identified crucial amino acid residues for inhibition against the HGF β-chain. By interfering with the HGF/Met interaction, these compounds may attenuate downstream signaling pathways involved in cancer cell proliferation and metastasis. Further optimization and comprehensive evaluations are necessary to advance these compounds toward clinical application in cancer therapy.
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Affiliation(s)
- Ko Suzuki
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
| | - Keitaro Inoue
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
| | - Ryota Namiguchi
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
| | - Seiya Morita
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
| | - Suzuho Hayakawa
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
| | - Mikuri Yokota
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
| | - Katsuya Sakai
- Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
- WPI-Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Japan
| | - Kunio Matsumoto
- WPI-Nano Life Science Institute, Kanazawa University, Kanazawa 920-1192, Japan
| | - Shunsuke Aoki
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, Japan
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Shelley CS, Galiègue-Zouitina S, Andritsos LA, Epperla N, Troussard X. The role of the JunD-RhoH axis in the pathogenesis of hairy cell leukemia and its ability to identify existing therapeutics that could be repurposed to treat relapsed or refractory disease. Leuk Lymphoma 2025; 66:637-655. [PMID: 39689307 DOI: 10.1080/10428194.2024.2438800] [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: 07/17/2024] [Revised: 11/19/2024] [Accepted: 12/01/2024] [Indexed: 12/19/2024]
Abstract
Hairy cell leukemia (HCL) is an indolent malignancy of mature B-lymphocytes. While existing front-line therapies achieve excellent initial results, a significant number of patients relapse and become increasingly treatment resistant. A major molecular driver of HCL is aberrant interlocking expression of the transcription factor JunD and the intracellular signaling molecule RhoH. Here we discuss the molecular basis of how the JunD-RhoH axis contributes to HCL pathogenesis. We also discuss how leveraging the JunD-RhoH axis identifies CD23, CD38, CD66a, CD115, CD269, integrin β7, and MET as new potential therapeutic targets. Critically, preclinical studies have already demonstrated that targeting CD38 with isatuximab effectively treats preexisiting HCL. Isatuximab and therapeutics directed against each of the other six new HCL targets are currently in clinical use to treat other disorders. Consequently, leveraging the JunD-RhoH axis has identified a battery of therapies that could be repurposed as new means of treating relapsed or refractory HCL.
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Affiliation(s)
| | | | - Leslie A Andritsos
- Division of Hematology Oncology, University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA
| | - Narendranath Epperla
- Division of Hematology, University of Utah Huntsman Cancer Institute, Salt Lake City, Utah, USA
| | - Xavier Troussard
- Hematology CHU Caen Normandie, INSERM1245, MICAH, Normandie University of Caen and Rouen, UNIROUEN, UNICAEN, Hematology Institute, University Hospital Caen, Caen, France
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Kounatidou NE, Vitkos E, Palioura S. Ocular surface squamous neoplasia: Update on genetics, epigenetics and opportunities for targeted therapy. Ocul Surf 2025; 35:1-14. [PMID: 39608452 DOI: 10.1016/j.jtos.2024.11.006] [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: 08/02/2024] [Revised: 11/09/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
PURPOSE The purpose of this review is to explore the molecular foundations of ocular surface squamous neoplasia (OSSN), focusing on the genetic and epigenetic aspects. While current management strategies include surgical excision and medical therapies, the understanding of OSSN's molecular basis remains limited, hindering the development of targeted treatments. METHODS A comprehensive MEDLINE search was conducted for literature published between January 1993 and October 2023. Only studies with original data on molecular, genetic, or epigenetic mechanisms, such as mutations, gene expression, and genetic predispositions were included. Articles were excluded if they focused solely on clinical management without addressing these factors, or if they were reviews, editorials, or opinion pieces. RESULTS The search yielded a total of 108 articles, out of which 39 articles met the criteria for further analysis. Investigations into OSSN have identified key DNA mutations in the TP53, HGF, EGFR, TERT, and CDKN2A genes, indicating common oncogenic pathways shared with other squamous cell carcinomas (SCCs). Significant epigenetic changes were identified, including DNA methylation, histone modifications, and altered miRNA expression patterns. Epigenetic dysregulation of critical tumor suppressors and oncoproteins, further highlight the complex genetic landscape of OSSN. CONCLUSION The molecular alterations identified in OSSN not only enhance our understanding of its biology but also have potential as novel biomarkers for early detection, prognostic evaluation, and as therapeutic targets. The identification of genetic and epigenetic markers in OSSN signifies progress towards personalized medicine approaches. Further studies and collaborative efforts are essential to validate these molecular markers and translate them into clinical practice, potentially revolutionizing OSSN management and improving patient outcomes.
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Affiliation(s)
| | - Evangelos Vitkos
- Department of Oral and Maxillofacial Surgery, Klinikum Dortmund, Dortmund, Germany
| | - Sotiria Palioura
- Department of Ophthalmology, University of Cyprus Medical School, Nicosia, Cyprus.
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Zhang D, Zhang W, Liu H, Liu P, Li C, Liu Y, Han J, Zhu G. Recent advances in the treatment of non-small cell lung cancer with MET inhibitors. Front Chem 2024; 12:1501844. [PMID: 39720556 PMCID: PMC11666382 DOI: 10.3389/fchem.2024.1501844] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 11/22/2024] [Indexed: 12/26/2024] Open
Abstract
Recently, research into the oncogenic driver genes associated with non-small cell lung cancer (NSCLC) has advanced significantly, leading to the development and clinical application of an increasing number of approved therapeutic agents. Among these, small molecule inhibitors that target mesenchymal-epithelial transition (MET) have demonstrated successful application in clinical settings. Currently, three categories of small molecule MET inhibitors, characterized by distinct binding patterns to the MET kinase region, have been developed: types Ia/Ib, II, and III. This review thoroughly examines MET's structure and its crucial role in NSCLC initiation and progression, explores discovery strategies for MET inhibitors, and discusses advancements in understanding resistance mechanisms. These insights are anticipated to enhance the development of a new generation of MET inhibitors characterized by high efficiency, selectivity, and low toxicity, thereby offering additional therapeutic alternatives for patients diagnosed with NSCLC.
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Affiliation(s)
- Dongna Zhang
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Wenying Zhang
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - He Liu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Pan Liu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Chunxin Li
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Yangyang Liu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Jicheng Han
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of integrative medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Guangze Zhu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
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Mer AH, Mirzaei Y, Misamogooe F, Bagheri N, Bazyari A, Keshtkaran Z, Meyfour A, Shahedi A, Amirkhani Z, Jafari A, Barpour N, Jahandideh S, Rezaei B, Nikmanesh Y, Abdollahpour-Alitappeh M. Progress of antibody-drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies. Drug Deliv Transl Res 2024; 14:2963-2988. [PMID: 38597995 DOI: 10.1007/s13346-024-01564-3] [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: 02/29/2024] [Indexed: 04/11/2024]
Abstract
The cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody-drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs.
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Affiliation(s)
- Ali Hussein Mer
- Department of Nursing, Mergasour Technical Institute, Erbil Polytechnic University, Erbil, Iraq
| | - Yousef Mirzaei
- Department of Medical Biochemical Analysis, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Fatemeh Misamogooe
- Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, 8813733450, Iran
| | - Ahmadreza Bazyari
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Keshtkaran
- Department of Nursing, School of Nursing and Midwifery, Community Based Psychiatric Care Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Shahedi
- Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran
| | - Zahra Amirkhani
- Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Barpour
- Department of Genetics, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Saeed Jahandideh
- Department of Research and Development, Orchidgene Co, Tehran, 1387837584, Iran
| | - Behzad Rezaei
- Laparoscopy Research Center, Department of Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars Province, Iran
| | - Yousef Nikmanesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Iweala EEJ, Amuji DN, Oluwajembola AM, Ugbogu EA. Targeting c-Met in breast cancer: From mechanisms of chemoresistance to novel therapeutic strategies. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2024; 7:100204. [PMID: 39524211 PMCID: PMC11543557 DOI: 10.1016/j.crphar.2024.100204] [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: 05/07/2024] [Revised: 09/28/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Breast cancer presents a significant challenge due to its heterogeneity and propensity for developing chemoresistance, particularly in the triple-negative subtype. c-Mesenchymal epithelial transition factor (c-Met), a receptor tyrosine kinase, presents a promising target for breast cancer therapy due to its involvement in disease progression and poor prognosis. However, the heterogeneous expression of c-Met within breast cancer subtypes and individual tumors complicates targeted therapy. Also, cancer cells can develop resistance to c-Met inhibitors through various mechanisms, including bypass signaling pathways and genetic mutations. The off-target effects of c-Met inhibitors further limit their clinical utility, necessitating the development of more selective agents. To overcome these challenges, personalized treatment approaches and combination therapies are being explored to improve treatment efficacy while minimizing adverse effects. Novel c-Met inhibitors with improved selectivity and reduced off-target toxicity show promise in preclinical studies. Additionally, targeted delivery systems aim to enhance drug localization and reduce systemic toxicity. Future directions involve refining inhibitor design and integrating c-Met inhibition into personalized treatment regimens guided by molecular profiling. This review explores the mechanisms by which c-Met contributes to chemoresistance in breast cancer and current challenges in targeting c-Met for breast cancer therapy. It discusses strategies to optimize treatment outcomes, ultimately improving patient prognosis and reducing mortality rates associated with this devastating disease.
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Affiliation(s)
- Emeka Eze Joshua Iweala
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
- Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Nigeria
| | - Doris Nnenna Amuji
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
- Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Nigeria
| | - Abimbola Mary Oluwajembola
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
- Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Covenant University, Ota, Nigeria
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Wang W, Huang C, Zhang L, Yu L, Liu Y, Wang P, Xia R. MST1R-targeted therapy in the battle against gallbladder cancer. Cell Biosci 2024; 14:109. [PMID: 39210450 PMCID: PMC11363441 DOI: 10.1186/s13578-024-01290-w] [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: 04/09/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Gallbladder cancer (GBC) is characterized by high mortality rate. Our study sought therapeutic candidates for GBC. RESULTS Bioinformatics analysis identified significant upregulation of MST1R in GBC. In vitro experiments demonstrated that the MST1R inhibitor MGCD-265 effectively restrained GBC cell proliferation at lower concentrations. Additionally, it induced cycle arrest and apoptosis in GBC cells in a dose-dependent manner. Mouse models exhibited that MGCD-265 treatment significantly diminished the proliferative capacity of GBC-SD cells. Transcriptomics sequencing revealed significant transcriptome alterations, with 200 transcripts upregulated and 883 downregulated. KEGG and GO analyses highlighted enrichment in processes like cell adhesion and pathways such as protein digestion and absorption. Downstream genes analysis identified JMJD6 upregulation post-MGCD-265 treatment. In vivo experiments confirmed that combining MGCD-265 with the JMJD6 inhibitor SKLB325 enhanced the anticancer effect against GBC. CONCLUSION Overall, targeting MST1R and its downstream genes, particularly combining MGCD-265 with SKLB325, holds promise as a therapeutic strategy for GBC.
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Affiliation(s)
- Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China.
| | - Chao Huang
- Department of Cell Biology, Medical School, Kunming University of Science and Technology, Kunming, 650500, China
| | - Li Zhang
- Department of Pathology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Liqin Yu
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Yangming Liu
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Puxiongzhi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Rongmu Xia
- Department of Gastroenterology, The Second Affiliated Hospital of Fujian, University of Traditional Chinese Medicine, Fuzhou, 350003, China
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Boschert V, Boenke J, Böhm AK, Teusch J, Steinacker V, Straub A, Hartmann S. Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling. Int J Mol Sci 2024; 25:7334. [PMID: 39000441 PMCID: PMC11242282 DOI: 10.3390/ijms25137334] [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: 05/17/2024] [Revised: 06/21/2024] [Accepted: 06/29/2024] [Indexed: 07/16/2024] Open
Abstract
Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune checkpoints operating in these non-responding tumors. To obtain an overview of which checkpoint ligands are expressed on HNSCC tumor cells and if these ligands are affected by HGF/MET signaling, we used mRNA sequencing and antibody-based techniques for identifying checkpoint ligands in six HNSCC tumor cell lines. Furthermore, we compared our results to mRNA sequencing data. From the checkpoint ligands we investigated, VISTA was expressed the highest at the RNA level and was also the most ubiquitously expressed. PD-L2 and B7-H3 were expressed comparably lower and were not present in all cell lines to the same extent. B7-H4, however, was only detectable in the Detroit 562 cell line. Concerning the effect of HGF on the ligand levels, PD-L2 expression was enhanced with HGF stimulation, whereas other checkpoint ligand levels decreased with stimulation. B7-H4 levels in the Detroit 562 cell line drastically decreased with HGF stimulation. This is of interest because both the checkpoint ligand and the growth factor are reported to be connected to epithelial-mesenchymal transition in the literature.
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Affiliation(s)
- Verena Boschert
- Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuerzburg, D-97070 Würzburg, Germany
| | | | | | | | | | | | - Stefan Hartmann
- Department of Oral and Maxillofacial Plastic Surgery, University Hospital Wuerzburg, D-97070 Würzburg, Germany
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 128.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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11
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Sabale P, Waghmare S, Potey L, Khedekar P, Sabale V, Rarokar N, Chikhale R, Palekar R. Novel targeting strategies on signaling pathways of colorectal cancer. COLORECTAL CANCER 2024:489-531. [DOI: 10.1016/b978-0-443-13870-6.00017-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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You L, Xin Z, Zhou X, Na F, Zhou J, Ying B. Diverse regulated cell death modes predict the immune microenvironment and drug sensitivity in lung adenocarcinoma. J Cell Physiol 2023; 238:2570-2585. [PMID: 37842875 DOI: 10.1002/jcp.31109] [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: 06/28/2023] [Revised: 08/05/2023] [Accepted: 08/16/2023] [Indexed: 10/17/2023]
Abstract
Integrated action modes of regulated cell death (RCD) in lung adenocarcinoma (LUAD) have not been comprehensively dissected. Here, we adopted 15 RCD modes, including 1350 related genes, and established RCD signature scores. We found that LUAD patients with high RCD scores had a significantly worse prognosis in all four different cohorts (TCGA, KM-plotter, GSE31210, and GSE30219). Our nomogram established based on the RCD score and clinical characteristics performed well in both the discovery and validation sets. There was a close correlation between the RCD scores and LUAD molecular subtypes identified by unsupervised consensus clustering. Furthermore, we profiled the tumor microenvironment via deconvolution and found significant differences in immune activity, transcription factor activity and molecular pathway enrichment between the RCD-high and RCD-low groups. More importantly, we revealed that the regulation of antigen presentation is the crucial mechanism underlying RCD. In addition, higher RCD scores predict poorer sensitivity to multiple therapeutic drugs, which indicates that RCD scores may serve as a promising predictor of chemotherapy and immunotherapy outcomes. In summary, this work is the first to reveal the internal links between RCD modes, LUAD, and cancer immunity and highlights the necessity of RCD scores in personalizing treatment plans.
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Affiliation(s)
- Liting You
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaodan Xin
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Feifei Na
- Department of Thoracic Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
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Yang MH, Lee M, Deivasigamani A, Le DD, Mohan CD, Hui KM, Sethi G, Ahn KS. Decanoic Acid Exerts Its Anti-Tumor Effects via Targeting c-Met Signaling Cascades in Hepatocellular Carcinoma Model. Cancers (Basel) 2023; 15:4681. [PMID: 37835375 PMCID: PMC10571573 DOI: 10.3390/cancers15194681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/01/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
DA, one of the medium-chain fatty acids found in coconut oil, is suggested to have diverse biochemical functions. However, its possible role as a chemoprevention agent in HCC has not been deciphered. Aberrant activation of c-Met can modulate tumor growth and progression in HCC. Here, we report that DA exhibited pro-found anti-tumor effects on human HCC through the suppression of HGF/c-Met signaling cascades in vitro and in vivo. It was noted that DA inhibited HGF-induced activation of c-Met and its downstream signals. DA induced apoptotic cell death and inhibited the expression of diverse tumorigenic proteins. In addition, DA attenuated tumor growth and lung metastasis in the HCC mouse model. Similar to in vitro studies, DA also suppressed the expression of c-Met and its downstream signals in mice tissues. These results highlight the substantial potential of DA in the prevention and treatment of HCC.
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Affiliation(s)
- Min Hee Yang
- Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Mina Lee
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si 57922, Republic of Korea; (M.L.); (D.D.L.)
| | - Amudha Deivasigamani
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; (A.D.); (K.M.H.)
| | - Duc Dat Le
- College of Pharmacy, Sunchon National University, 255 Jungangno, Suncheon-si 57922, Republic of Korea; (M.L.); (D.D.L.)
| | - Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India;
| | - Kam Man Hui
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore 169610, Singapore; (A.D.); (K.M.H.)
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
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14
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Wang B, Liu W, Liu C, Du K, Guo Z, Zhang G, Huang Z, Lin S, Cen B, Tian Y, Yuan Y, Bu J. Cancer-Associated Fibroblasts Promote Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling Pathway. Int J Radiat Oncol Biol Phys 2022:S0360-3016(22)03679-3. [PMID: 36586496 DOI: 10.1016/j.ijrobp.2022.12.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 12/10/2022] [Accepted: 12/17/2022] [Indexed: 12/30/2022]
Abstract
PURPOSE Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment (TME), which is involved in therapy resistance. This study aimed to investigate the role of CAFs in radiosensitivity of breast cancer cells. METHODS AND MATERIALS The CAFs were isolated from the breast cancer tissues, and the conditioned medium was collected to culture breast cancer cells. Radiation-induced DNA damage was evaluated by immunofluorescence and western blotting. Cytokine array and enzyme-linked immunosorbent assay were performed to analyze the secretion of cytokines and growth factors. An in vitro clonogenic survival assay and in vivo xenograft mouse model were performed to determine the radiosensitivity of breast cancer cells. Finally, the expression of hepatocyte growth factor (HGF) and c-Met in the breast cancer tissues were detected by immunohistochemistry. RESULTS The CAFs were found to secrete HGF to activate the c-Met signaling pathway, which induced epithelial-to-mesenchymal transition, growth, and radioresistance of breast cancer cells. Furthermore, radiation was observed to enhance HGF secretion by CAFs and increase c-Met expression in breast cancer cells, which led to HGF/c-Met signaling pathway activation. Moreover, radiation-induced tumor necrosis factor α (TNFα) secretion by breast cancer cells promoted CAF proliferation and HGF secretion. Additionally, HGF and c-Met high expression were associated with worse recurrence-free survival in patients with breast cancer who had received radiation therapy. CONCLUSIONS The findings revealed that HGF and TNFα are critical for the crosstalk between breast cancer cells and CAFs in the TME and that the HGF/c-Met signaling pathway is a promising therapeutic target for radiosensitizing breast cancer.
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Affiliation(s)
- Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Wei Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Chunshan Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Kunpeng Du
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Zhaoze Guo
- Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Guoqian Zhang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Zhong Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Shuhui Lin
- Department of Oncology, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen, Guangdong Province, China
| | - Bohong Cen
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yunhong Tian
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, China; Department of Oncology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong Province, China.
| | - Junguo Bu
- Department of Oncology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong Province, China.
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15
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Mesquita BS, Fens MHAM, Di Maggio A, Bosman EDC, Hennink WE, Heger M, Oliveira S. The Impact of Nanobody Density on the Targeting Efficiency of PEGylated Liposomes. Int J Mol Sci 2022; 23:ijms232314974. [PMID: 36499301 PMCID: PMC9741042 DOI: 10.3390/ijms232314974] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022] Open
Abstract
Nanoparticles (NPs) are commonly modified with tumor-targeting moieties that recognize proteins overexpressed on the extracellular membrane to increase their specific interaction with target cells. Nanobodies (Nbs), the variable domain of heavy chain-only antibodies, are a robust targeting ligand due to their small size, superior stability, and strong binding affinity. For the clinical translation of targeted Nb-NPs, it is essential to understand how the number of Nbs per NP impacts the receptor recognition on cells. To study this, Nbs targeting the hepatocyte growth factor receptor (MET-Nbs) were conjugated to PEGylated liposomes at a density from 20 to 800 per liposome and their targeting efficiency was evaluated in vitro. MET-targeted liposomes (MET-TLs) associated more profoundly with MET-expressing cells than non-targeted liposomes (NTLs). MET-TLs with approximately 150-300 Nbs per liposome exhibited the highest association and specificity towards MET-expressing cells and retained their targeting capacity when pre-incubated with proteins from different sources. Furthermore, a MET-Nb density above 300 Nbs per liposome increased the interaction of MET-TLs with phagocytic cells by 2-fold in ex vivo human blood compared to NTLs. Overall, this study demonstrates that adjusting the MET-Nb density can increase the specificity of NPs towards their intended cellular target and reduce NP interaction with phagocytic cells.
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Affiliation(s)
- Bárbara S. Mesquita
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Marcel H. A. M. Fens
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Alessia Di Maggio
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Esmeralda D. C. Bosman
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Wim E. Hennink
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
| | - Michal Heger
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314041, China
- Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Department of Chemistry, Utrecht University, 3584 CG Utrecht, The Netherlands
- Correspondence: (M.H.); (S.O.)
| | - Sabrina Oliveira
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Science Faculty, Utrecht University, 3584 CG Utrecht, The Netherlands
- Correspondence: (M.H.); (S.O.)
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16
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Lou H, Cao X. Antibody variable region engineering for improving cancer immunotherapy. Cancer Commun (Lond) 2022; 42:804-827. [PMID: 35822503 PMCID: PMC9456695 DOI: 10.1002/cac2.12330] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/25/2022] [Accepted: 06/22/2022] [Indexed: 04/09/2023] Open
Abstract
The efficacy and specificity of conventional monoclonal antibody (mAb) drugs in the clinic require further improvement. Currently, the development and application of novel antibody formats for improving cancer immunotherapy have attracted much attention. Variable region-retaining antibody fragments, such as antigen-binding fragment (Fab), single-chain variable fragment (scFv), bispecific antibody, and bi/trispecific cell engagers, are engineered with humanization, multivalent antibody construction, affinity optimization and antibody masking for targeting tumor cells and killer cells to improve antibody-based therapy potency, efficacy and specificity. In this review, we summarize the application of antibody variable region engineering and discuss the future direction of antibody engineering for improving cancer therapies.
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Affiliation(s)
- Hantao Lou
- Ludwig Institute of Cancer ResearchUniversity of OxfordOxfordOX3 7DRUK
- Chinese Academy for Medical Sciences Oxford InstituteNuffield Department of MedicineUniversity of OxfordOxfordOX3 7FZUK
| | - Xuetao Cao
- Chinese Academy for Medical Sciences Oxford InstituteNuffield Department of MedicineUniversity of OxfordOxfordOX3 7FZUK
- Department of ImmunologyCentre for Immunotherapy, Institute of Basic Medical SciencesChinese Academy of Medical SciencesBeijing100005P. R. China
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17
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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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De Herdt MJ, van der Steen B, Baatenburg de Jong RJ, Looijenga LHJ, Koljenović S, Hardillo JA. The Occurrence of MET Ectodomain Shedding in Oral Cancer and Its Potential Impact on the Use of Targeted Therapies. Cancers (Basel) 2022; 14:cancers14061491. [PMID: 35326642 PMCID: PMC8946088 DOI: 10.3390/cancers14061491] [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: 12/28/2021] [Revised: 02/18/2022] [Accepted: 03/10/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Head and neck cancer is the sixth most common cancer type worldwide, comprising tumors of the upper aero/digestive tract. Approximately 50% of these cancers originate in the oral cavity. Depending on disease stage, oral cancer patients are treated with single-modality surgery, or in combination with radiotherapy with or without chemotherapy. Despite advances in these modalities, the 5-year survival rate is merely 50%. Therefore, implementation of targeted therapies, directed against signaling molecules, has gained attention. One potential target is the MET protein, which can be present on the surface of cancer cells, orchestrating aggressive behavior. As cancer cells can shed the extracellular part of MET from their surface, it is important to identify for MET positive patients whether they possess the entire and/or only the intracellular part of the receptor to assess whether targeted therapies directed against the extracellular, intracellular, or both parts of MET need to be implemented. Abstract The receptor tyrosine kinase MET has gained attention as a therapeutic target. Although MET immunoreactivity is associated with progressive disease, use of targeted therapies has not yet led to major survival benefits. A possible explanation is the lack of companion diagnostics (CDx) that account for proteolytic processing. During presenilin-regulated intramembrane proteolysis, MET’s ectodomain is shed into the extracellular space, which is followed by γ-secretase-mediated cleavage of the residual membranous C-terminal fragment. The resulting intracellular fragment is degraded by the proteasome, leading to downregulation of MET signaling. Conversely, a membrane-bound MET fragment lacking the ectodomain (MET-EC-) can confer malignant potential. Use of C- and N-terminal MET monoclonal antibodies (moAbs) has illustrated that MET-EC- occurs in transmembranous C-terminal MET-positive oral squamous cell carcinoma (OSCC). Here, we propose that ectodomain shedding, resulting from G-protein-coupled receptor transactivation of epidermal growth factor receptor signaling, and/or overexpression of ADAM10/17 and/or MET, stabilizes and possibly activates MET-EC- in OSCC. As MET-EC- is associated with poor prognosis in OSCC, it potentially has impact on the use of targeted therapies. Therefore, MET-EC- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Hence, MET-EC- requires further investigation seen its oncogenic and predictive properties.
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Affiliation(s)
- Maria J. De Herdt
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
- Correspondence: ; Tel.: +31-10-7044490
| | - Berdine van der Steen
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
| | - Robert J. Baatenburg de Jong
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
| | - Leendert H. J. Looijenga
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands;
- Department of Pathology, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
| | - Senada Koljenović
- Department of Pathology, Antwerp University Hospital, 2650 Edegem, Belgium;
| | - Jose A. Hardillo
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Cancer Institute, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (B.v.d.S.); (R.J.B.d.J.); (J.A.H.)
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19
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Zupanič N, Počič J, Leonardi A, Šribar J, Kordiš D, Križaj I. Serine pseudoproteases in physiology and disease. FEBS J 2022; 290:2263-2278. [PMID: 35032346 DOI: 10.1111/febs.16355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/20/2021] [Accepted: 01/12/2022] [Indexed: 01/01/2023]
Abstract
Serine proteases (SPs) constitute a very important family of enzymes, both physiologically and pathologically. The effects produced by these proteins have been explained by their proteolytic activity. However, the discovery of pharmacologically active SP molecules that show no enzymatic activity, as the so-called pseudo SPs or SP homologs (SPHs), has exposed a profoundly neglected possibility of nonenzymatic functions of these SP molecules. In this review, the most thoroughly described SPHs are presented. The main physiological domains in which SPHs operate appear to be in reproduction, embryonic development, immune response, host defense, and hemostasis. Hitherto unexplained actions of SPs should therefore be considered also as the result of the ligand-like attributes of SPs. The gain of a novel function by an SPH is a consequence of specific amino acid replacements that have resulted in a novel interaction interface or a 'catalytic trap'. Unraveling the SP/SPH interactome will provide a description of previously unknown physiological functions of SPs/SPHs, aiding the creation of innovative medical approaches.
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Affiliation(s)
- Nina Zupanič
- Department of Molecular and Biomedical Sciences Jožef Stefan Institute Ljubljana Slovenia
| | - Jernej Počič
- Department of Molecular and Biomedical Sciences Jožef Stefan Institute Ljubljana Slovenia
- Biotechnical Faculty University of Ljubljana Slovenia
| | - Adrijana Leonardi
- Department of Molecular and Biomedical Sciences Jožef Stefan Institute Ljubljana Slovenia
| | - Jernej Šribar
- Department of Molecular and Biomedical Sciences Jožef Stefan Institute Ljubljana Slovenia
| | - Dušan Kordiš
- Department of Molecular and Biomedical Sciences Jožef Stefan Institute Ljubljana Slovenia
| | - Igor Križaj
- Department of Molecular and Biomedical Sciences Jožef Stefan Institute Ljubljana Slovenia
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20
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Grundy M, Narendran A. The hepatocyte growth factor/mesenchymal epithelial transition factor axis in high-risk pediatric solid tumors and the anti-tumor activity of targeted therapeutic agents. Front Pediatr 2022; 10:910268. [PMID: 36034555 PMCID: PMC9399617 DOI: 10.3389/fped.2022.910268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/15/2022] [Indexed: 01/04/2023] Open
Abstract
Clinical trials completed in the last two decades have contributed significantly to the improved overall survival of children with cancer. In spite of these advancements, disease relapse still remains a significant cause of death in this patient population. Often, increasing the intensity of current protocols is not feasible because of cumulative toxicity and development of drug resistance. Therefore, the identification and clinical validation of novel targets in high-risk and refractory childhood malignancies are essential to develop effective new generation treatment protocols. A number of recent studies have shown that the hepatocyte growth factor (HGF) and its receptor Mesenchymal epithelial transition factor (c-MET) influence the growth, survival, angiogenesis, and metastasis of cancer cells. Therefore, the c-MET receptor tyrosine kinase and HGF have been identified as potential targets for cancer therapeutics and recent years have seen a race to synthesize molecules to block their expression and function. In this review we aim to summarize the literature that explores the potential and biological rationale for targeting the HGF/c-MET pathway in common and high-risk pediatric solid tumors. We also discuss selected recent and ongoing clinical trials with these agents in relapsed pediatric tumors that may provide applicable future treatments for these patients.
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Affiliation(s)
- Megan Grundy
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Aru Narendran
- POETIC Laboratory for Preclinical and Drug Discovery Studies, Division of Pediatric Oncology, Alberta Children's Hospital, University of Calgary, Calgary, AB, Canada
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21
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Mehraj U, Ganai RA, Macha MA, Hamid A, Zargar MA, Bhat AA, Nasser MW, Haris M, Batra SK, Alshehri B, Al-Baradie RS, Mir MA, Wani NA. The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: New challenges and therapeutic opportunities. Cell Oncol (Dordr) 2021; 44:1209-1229. [PMID: 34528143 DOI: 10.1007/s13402-021-00634-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. The tumor microenvironment (TME), comprising cellular components, such as cancer-associated fibroblasts (CAFs), immune cells, endothelial cells and adipocytes, and noncellular components such as extracellular matrix (ECM), has been recognized as a critical contributor to the development and progression of BC. The interplay between TME components and cancer cells promotes phenotypic heterogeneity, cell plasticity and cancer cell stemness that impart tumor dormancy, enhanced invasion and metastasis, and the development of therapeutic resistance. While most previous studies have focused on targeting cancer cells with a dismal prognosis, novel therapies targeting stromal components are currently being evaluated in preclinical and clinical studies, and are already showing improved efficacies. As such, they may offer better means to eliminate the disease effectively. CONCLUSIONS In this review, we focus on the evolving concept of the TME as a key player regulating tumor growth, metastasis, stemness, and the development of therapeutic resistance. Despite significant advances over the last decade, several clinical trials focusing on the TME have failed to demonstrate promising effectiveness in cancer patients. To expedite clinical efficacy of TME-directed therapies, a deeper understanding of the TME is of utmost importance. Secondly, the efficacy of TME-directed therapies when used alone or in combination with chemo- or radiotherapy, and the tumor stage needs to be studied. Likewise, identifying molecular signatures and biomarkers indicating the type of TME will help in determining precise TME-directed therapies.
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Affiliation(s)
- Umar Mehraj
- Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India
| | - Rais A Ganai
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science & Technology , Awantipora, Jammu & Kashmir, India
| | - Abid Hamid
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Mohammed A Zargar
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory of Animal Research, Qatar University, Doha, Qatar
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Lincoln, NE, USA.,Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia
| | - Raid Saleem Al-Baradie
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Almajmaah, Kingdom of Saudi Arabia
| | - Manzoor A Mir
- Department of Bioresources, University of Kashmir, Srinagar, Jammu & Kashmir, India.
| | - Nissar Ahmad Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, J&K, India.
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22
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Meng W, Chen T. Association between the HGF/c‑MET signaling pathway and tumorigenesis, progression and prognosis of hepatocellular carcinoma (Review). Oncol Rep 2021; 46:191. [PMID: 34278495 DOI: 10.3892/or.2021.8142] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/10/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive and lethal malignancies with a rising incidence, and is characterized by rapid progression, frequent metastasis, late diagnosis, high postoperative recurrence and poor prognosis. Therefore, novel treatment strategies for HCC, particularly advanced HCC, are urgently required. The hepatocyte growth factor (HGF)/c‑mesenchymal‑epithelial transition receptor (c‑MET) axis is a key signaling pathway in HCC and is strongly associated with its highly malignant features. Available treatments based on HGF/c‑MET inhibition may prolong the lifespan of patients with HCC; however, they do not achieve the desired therapeutic effects. The aim of the present article was to review the basic knowledge regarding the role of the HGF/c‑MET signaling pathway in HCC, and examine the association between the HGF/c‑MET signaling pathway and the tumorigenesis, progression and prognosis of HCC.
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Affiliation(s)
- Wei Meng
- School of Medicine, China Three Gorges University, Yichang, Hubei 443002, P.R. China
| | - Tao Chen
- School of Medicine, China Three Gorges University, Yichang, Hubei 443002, P.R. China
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23
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Lee M, Jain P, Wang F, Ma PC, Borczuk A, Halmos B. MET alterations and their impact on the future of non-small cell lung cancer (NSCLC) targeted therapies. Expert Opin Ther Targets 2021; 25:249-268. [PMID: 33945380 DOI: 10.1080/14728222.2021.1925648] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: The MET gene and its pathway normally plays a crucial role in cell homeostasis, motility, and apoptosis. However, when the MET gene is altered, there is an imbalance toward cell proliferation and invasion commonly seen in numerous different types of cancers. The heterogeneous group of MET alterations that includes MET amplification, MET exon 14 skipping mutation, and MET fusions has been difficult to diagnose and treat. Currently, treatments are focused on tyrosine kinase inhibitors but now there is emerging data on novel MET-targeted therapies including monoclonal antibodies and antibody-drug conjugates that have emerged.Areas covered: We introduce new emerging data on MET alterations in non-small cell lung cancer (NSCLC) that has contributed to advances in MET targeted therapeutics. We offer our perspective and examine new information on the mechanisms of the MET alterations in this review.Expert opinion: Given the trends currently involving the targeting of MET altered malignancies, there will most likely be a continued rapid expansion of testing, novel tyrosine kinase inhibitors and potent antibody approaches. Combination treatments will be necessary to optimize management of advanced and early disease.
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Affiliation(s)
- Matthew Lee
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Prantesh Jain
- Division of Medical Oncology, Department of Medicine, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Feng Wang
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Patrick C Ma
- Penn State CancerInstitute, PennState College of Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA
| | - Alain Borczuk
- Department of Pathology, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA
| | - Balazs Halmos
- Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
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24
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Aftimos P, Rolfo C, Rottey S, Barthélémy P, Borg C, Park K, Oh DY, Kim SW, De Jonge N, Hanssens V, Zwanenpoel K, Molthoff C, Vugts D, Dreier T, Verheesen P, van Dongen GA, Jacobs J, Van Rompaey L, Hultberg A, Michieli P, Pauwels P, Fung S, Thibault A, de Haard H, Leupin N, Awada A. The NHance ® Mutation-Equipped Anti-MET Antibody ARGX-111 Displays Increased Tissue Penetration and Anti-Tumor Activity in Advanced Cancer Patients. Biomedicines 2021; 9:biomedicines9060665. [PMID: 34200749 PMCID: PMC8229762 DOI: 10.3390/biomedicines9060665] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/27/2021] [Accepted: 06/08/2021] [Indexed: 11/25/2022] Open
Abstract
Dysregulation of MET signaling has been implicated in tumorigenesis and metastasis. ARGX-111 combines complete blockade of this pathway with enhanced tumor cell killing and was investigated in 24 patients with MET-positive advanced cancers in a phase 1b study at four dose levels (0.3–10 mg/kg). ARGX-111 was well tolerated up to 3 mg/kg (MTD). Anti-tumor activity was observed in nearly half of the patients (46%) with a mean duration of treatment of 12 weeks. NHance® mutations in the Fc of ARGX-111 increased affinity for the neonatal Fc receptor (FcRn) at acidic pH, stimulating transcytosis across FcRn-expressing cells and radiolabeled ARGX-111 accumulated in lymphoid tissues, bone and liver, organs expressing FcRn at high levels in a biodistribution study using human FcRn transgenic mice. In line with this, we observed, in a patient with MET-amplified (>10 copies) gastric cancer, diminished metabolic activity in multiple metastatic lesions in lymphoid and bone tissues by 18F-FDG-PET/CT after two infusions with 0.3 mg/kg ARGX-111. When escalated to 1 mg/kg, a partial response was reached. Furthermore, decreased numbers of CTC (75%) possibly by the enhanced tumor cell killing witnessed the modes of action of the drug, warranting further clinical investigation of ARGX-111.
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Affiliation(s)
- Philippe Aftimos
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (P.A.); (A.A.)
| | - Christian Rolfo
- University Hospital Antwerp, 2650 Edegem, Belgium; (C.R.); (K.Z.); (P.P.)
| | | | - Philippe Barthélémy
- Medical Oncology Unit, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France;
| | - Christophe Borg
- Medical Oncology Department, University Hospital of Besançon, CEDEX, 25000 Besançon, France;
| | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Do-Youn Oh
- Seoul National University Hospital, Seoul 03080, Korea;
| | - Sang-We Kim
- Asan Medical Center, Department of Oncology, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Natalie De Jonge
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Valérie Hanssens
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Karen Zwanenpoel
- University Hospital Antwerp, 2650 Edegem, Belgium; (C.R.); (K.Z.); (P.P.)
| | - Carla Molthoff
- Department of Radiology & Nuclear Medicine, VU University Medical Center Amsterdam, 1012 Amsterdam, The Netherlands; (C.M.); (D.V.); (G.A.M.S.v.D.)
| | - Daniëlle Vugts
- Department of Radiology & Nuclear Medicine, VU University Medical Center Amsterdam, 1012 Amsterdam, The Netherlands; (C.M.); (D.V.); (G.A.M.S.v.D.)
| | - Torsten Dreier
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
- AgomAb Therapeutics NV, 9000 Ghent, Belgium;
| | - Peter Verheesen
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Guus A.M.S. van Dongen
- Department of Radiology & Nuclear Medicine, VU University Medical Center Amsterdam, 1012 Amsterdam, The Netherlands; (C.M.); (D.V.); (G.A.M.S.v.D.)
| | - Julie Jacobs
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Luc Van Rompaey
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Anna Hultberg
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Paolo Michieli
- AgomAb Therapeutics NV, 9000 Ghent, Belgium;
- Department of Oncology, University of Torino Medical School, 10124 Turin, Italy
| | - Patrick Pauwels
- University Hospital Antwerp, 2650 Edegem, Belgium; (C.R.); (K.Z.); (P.P.)
| | - Samson Fung
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Alain Thibault
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Hans de Haard
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
| | - Nicolas Leupin
- Argenx BV, Industriepark Zwijnaarde 7, 9052 Ghent, Belgium; (N.D.J.); (V.H.); (T.D.); (P.V.); (J.J.); (L.V.R.); (A.H.); (S.F.); (A.T.); (H.d.H.)
- Correspondence: ; Tel.: +41-79-293-18-14
| | - Ahmad Awada
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (P.A.); (A.A.)
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25
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Wang S, Ma H, Yan Y, Chen Y, Fu S, Wang J, Wang Y, Chen H, Liu J. cMET promotes metastasis and epithelial-mesenchymal transition in colorectal carcinoma by repressing RKIP. J Cell Physiol 2021; 236:3963-3978. [PMID: 33151569 DOI: 10.1002/jcp.30142] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 10/01/2020] [Accepted: 10/23/2020] [Indexed: 02/05/2023]
Abstract
Increasing evidence indicates that c-mesenchymal-epithelial transition factor (cMET) plays an important role in the malignant progression of colorectal cancer (CRC). However, the underlying mechanism is not fully understood. As a metastasis suppressor, raf kinase inhibitory protein (RKIP) loss has been reported in many cancer types. In this study, the expression levels of cMET and RKIP in CRC tissues and cell lines were determined, and their crosstalk and potential biological effects were explored in vitro and in vivo. Our results showed that cMET was inversely correlated with RKIP. Both cMET upregulation and RKIP downregulation indicated poor clinical outcomes. Moreover, the MAPK/ERK signaling pathway was implicated in the regulation of cMET and RKIP. Overexpression of cMET promoted tumor cell epithelial-mesenchymal transition, invasion, migration, and chemoresistance, whereas the effects could be efficiently inhibited by increased RKIP. Notably, small hairpin RNA-mediated cMET knockdown dramatically suppressed cell proliferation, although no RKIP-induced influence on cell growth was observed in CRC. Altogether, cMET overexpression may contribute to tumor progression by inhibiting the antioncogene RKIP, providing preclinical justification for targeting RKIP to treat cMET-induced metastasis of CRC.
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Affiliation(s)
- Siyun Wang
- Department of PET Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Haiqing Ma
- Department of Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Yan Yan
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
| | - Yu Chen
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Sirui Fu
- Department of Interventional Therapy, Zhuhai Interventional Medical Center, Zhuhai City People's Hospital/Zhuhai Hospital of Jinan University, Zhuhai, Guangdong, China
| | - Junjiang Wang
- Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Ying Wang
- Department of Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Jianhua Liu
- Department of Oncology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Southern Medical University, Guangzhou, Guangdong, China
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26
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Moosavi F, Giovannetti E, Peters GJ, Firuzi O. Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer. Crit Rev Oncol Hematol 2021; 160:103234. [PMID: 33497758 DOI: 10.1016/j.critrevonc.2021.103234] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 12/29/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023] Open
Abstract
MET receptor has emerged as a druggable target across several human cancers. Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping. In this review, we critically examine the current evidence on how HGF/MET combination therapies may take advantage of synergistic effects, overcome primary or acquired drug resistance, target tumor microenvironment, modulate drug metabolism or tackle pharmacokinetic issues. Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (including EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients.
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Affiliation(s)
- Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa, Italy
| | - Godefridus J Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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27
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Garon EB, Brodrick P. Targeted Therapy Approaches for MET Abnormalities in Non-Small Cell Lung Cancer. Drugs 2021; 81:547-554. [PMID: 33638808 DOI: 10.1007/s40265-021-01477-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2021] [Indexed: 12/18/2022]
Abstract
The tyrosine kinase receptor mesenchymal epithelial transition (MET) is a proto-oncogene that, through the activation of the MET-hepatocyte growth factor (HGF) pathway, encodes a variety of biological processes, including cell development, proliferation, invasion, and migration. Abnormal activation of the MET pathway, occurring through MET protein overexpression, and gene amplification or mutation, can contribute to oncogenesis and has been implicated in non-small cell lung cancer (NSCLC). Though it is associated with poor clinical outcome in NSCLCs, MET overexpression and its role as a therapeutic target remains somewhat elusive due to discrepancies in its occurrence. Unlike MET overexpression, MET amplification has demonstrated a stronger potential as a biomarker for therapeutic treatment, with clinical data indicating a compelling connection between a high MET gene copy number and a high response rate to targeted therapies. However, MET exon 14 skipping mutations, occurring in 3%-4 % of lung adenocarcinomas, are of particular interest, as tumors harboring these mutations have shown a significant response to MET inhibitors. Following the discovery of MET as a potential therapeutic target, extensive clinical studies have proposed three approaches to targeting MET: (1) MET tyrosine kinase inhibitors (TKIs), including crizotinib, capmatinib, tepotinib, savolinitib, and cabozantinib; (2) MET or HGF monoclonal antibodies, including emibetuzumab and ficlatuzumab; and (3) MET or HGF antibody drug conjugates, including telisotuzumab. Herein, we discuss the relevant clinical trials, particularly focusing on the efficacy as well as the safety and tolerability of the treatment options, in the promising field of targeting MET in NSCLC.
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Affiliation(s)
- Edward B Garon
- David Geffen School of Medicine at the University of California, Los Angeles, CA, USA
| | - Paige Brodrick
- David Geffen School of Medicine at the University of California, Los Angeles, CA, USA.
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28
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Hwang K, Yoon JH, Lee JH, Lee S. Recent Advances in Monoclonal Antibody Therapy for Colorectal Cancers. Biomedicines 2021; 9:39. [PMID: 33466394 PMCID: PMC7824816 DOI: 10.3390/biomedicines9010039] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. Recent advances in recombinant DNA technology have led to the development of numerous therapeutic antibodies as major sources of blockbuster drugs for CRC therapy. Simultaneously, increasing numbers of therapeutic targets in CRC have been identified. In this review, we first highlight the physiological and pathophysiological roles and signaling mechanisms of currently known and emerging therapeutic targets, including growth factors and their receptors as well as immune checkpoint proteins, in CRC. Additionally, we discuss the current status of monoclonal antibodies in clinical development and approved by US Food and Drug Administration for CRC therapy.
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Affiliation(s)
| | | | | | - Sukmook Lee
- Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, Seoul 02707, Korea; (K.H.); (J.H.Y.); (J.H.L.)
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29
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Roth KG, Mambetsariev I, Salgia R. Prolonged survival and response to tepotinib in a non-small-cell lung cancer patient with brain metastases harboring MET exon 14 mutation: a research report. Cold Spring Harb Mol Case Stud 2020; 6:a005785. [PMID: 33335011 PMCID: PMC7784494 DOI: 10.1101/mcs.a005785] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/24/2020] [Indexed: 01/04/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have transformed the standard of care in lung cancer. A number of TKIs have been discovered that specifically target oncogenes, including MET receptor tyrosine kinase. Second-generation MET TKIs are showing improved efficacy over first-generation TKIs. Herein, we report a case of a patient with metastatic lung adenocarcinoma harboring a MET exon 14 splice site mutation who has had prolonged disease control by a second-generation MET-TKI tepotinib. A 66-yr-old man was diagnosed with stage IV lung adenocarcinoma. He was started on carboplatin, paclitaxel, and bevacizumab, but had severe toxicity. He was switched to pembrolizumab as his tumor was PD-L1 70%, and molecular testing was not yet performed because of insufficient tissue. A bronchoscopy with endobronchial ultrasound was performed and a MET exon 14 splice site mutation was detected by next-generation sequencing. Upon progression, he was then enrolled in a clinical trial of tepotinib and continues with stable disease for more than 45 cycles and 31 mo. The MET receptor tyrosine kinase and the ligand hepatocyte growth factor (HGF) have been implicated as oncogenes and drivers of non-small-cell lung cancer (NSCLC). Newer MET TKIs including capmatinib and tepotinib more recently showed not only improved localized control and response, but early data suggests intracranial activity as compared to first-generation MET TKIs, both in the front-line and the refractory setting. This is a case report demonstrating an effective duration of response in a patient with widely metastatic lung adenocarcinoma harboring a MET exon 14 mutation.
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Affiliation(s)
- Katherine G Roth
- Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California 91010, USA
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California 91010, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California 91010, USA
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30
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Yang SY, Yang KC, Sumi S. Prevascularization-free Primary Subcutaneous Transplantation of Xenogeneic Islets Coencapsulated With Hepatocyte Growth Factor. Transplant Direct 2020; 6:e620. [PMID: 33134496 PMCID: PMC7587419 DOI: 10.1097/txd.0000000000001078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 08/31/2020] [Accepted: 09/18/2020] [Indexed: 01/13/2023] Open
Abstract
Subcutaneous pouch is a potential site for islet transplantation. However, insufficient oxygen supply remains challenging. Pretreatment of neovascularization using basic fibroblast growth factor can solve this, but it needs 2× operations. We developed a device that contains rat islets in chitosan gel packed in a bag made of highly biocompatible ethylene vinyl alcohol copolymer porous membrane. This study investigated whether coencapsulation of hepatocyte growth factor (HGF) with islets in the device enables novel method of prevascularization-free primary subcutaneous transplantation. METHODS In vitro experiments examined slow release of HGF from the chitosan gel and islet-protection effect of HGF against hypoxia. In the latter, rat islets with/without HGF (200 ng/mL) was cultured in 1% oxygen. In in vivo experiment, fabricated device with/without HGF (10 μg/device) containing rat islets was primarily transplanted to streptozotocin-induced diabetic mice subcutaneously. RESULTS In vitro experiments showed sustained release of HGF for 28 d and alleviating effect of HGF on cell death and glucose-responsive insulin release after hypoxic culture. Islet + HGF mice, but not islet-alone mice, showed decreased nonfasting blood glucose and regained body weight after transplantation. In intraperitoneal glucose tolerance test, islet + HGF mice exhibited decreased fasting blood glucose (200 ± 55 mg/dL) and good blood glucose disappearance rate (K value) (0.817 ± 0.101) comparing to normal mice (123 ± 28 mg/dL and 1.074 ± 0.374, respectively). However, in islet-alone mice, fasting blood glucose was high (365 ± 172 mg/dL) and K value was indeterminable. Serum insulin in islet + HGF mice (1.58 ± 0.94 μg/L) was close to normal mice (1.66 ± 0.55 μg/L), whereas those in islet-alone mice (0.279 ± 0.076 μg/L) and diabetic mice (0.165 ± 0.079 μg/L) were low. Immunohistochemical examination showed intact insulin- and glucagon-positive islets in retrieved devices with HGF, but no intact islet was found in the device without HGF. CONCLUSIONS HGF could enhance islet survival in hypoxia and enhance in vivo function of encapsulated islets after primary subcutaneous transplantation.
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Affiliation(s)
- Sin-Yu Yang
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Kai-Chiang Yang
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shoichiro Sumi
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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31
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Li J, Hu K, Zhou L, Huang J, Zeng S, Xu Z, Yan Y. Spectrum of Mesenchymal-Epithelial Transition Aberrations and Potential Clinical Implications: Insights From Integrative Pancancer Analysis. Front Oncol 2020; 10:560615. [PMID: 33178590 PMCID: PMC7593712 DOI: 10.3389/fonc.2020.560615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/16/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The receptor tyrosine kinase mesenchymal-epithelial transition factor (MET) is frequently altered in cancers and is a common therapeutic target for cancers with MET variants. However, abnormal MET alterations and their associations with patient outcome across different cancer types have not been studied simultaneously. In this study, we try to fill the vacancy in a comprehensive manner and capture the full MET alteration spectrum. METHODS A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs). RESULTS MET abnormal expression, alteration frequency, mutation site distribution, and functional impact varied across different cancer types. Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis. Kidney renal papillary cell carcinoma (KIRP) harbored the third highest alteration frequency of MET, which was dominated by mutations. While most mutations were in the Pkinase_Tyr domain, a few were targetable. Pancreatic adenocarcinoma (PAAD) harbors very few alterations, but increased MET expression is associated with poor outcomes. Esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), and ovarian serous cystadenocarcinoma (OV) had similar characteristics: a high frequency of MET CNVs but relatively few MET mutations, and high MET expression associated with poor prognosis. CONCLUSION This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.
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Affiliation(s)
- Juanni Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Kuan Hu
- Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Zhou
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Jinzhou Huang
- Department of Oncology, Mayo Clinic, Rochester, MN, United States
| | - Shuangshuang Zeng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020; 5:230. [PMID: 33028805 PMCID: PMC7542154 DOI: 10.1038/s41392-020-00324-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yongsheng Li
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Rong Shao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Fatao Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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Yao HP, Tong XM, Hudson R, Wang MH. MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy. J Exp Clin Cancer Res 2020; 39:198. [PMID: 32962738 PMCID: PMC7510328 DOI: 10.1186/s13046-020-01711-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future.
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Affiliation(s)
- Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China.
| | - Xiang-Min Tong
- Department of Hematology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
| | - Rachel Hudson
- Cancer Biology Research Center, Texas Tech University Health Sciences Center, Amarillo, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, TX, Amarillo, USA
| | - Ming-Hai Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- National Clinical Research Center for Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Biology Research Center, Texas Tech University Health Sciences Center, Amarillo, USA.
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, TX, Amarillo, USA.
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Chaudhary SP, Kwak EL, Hwang KL, Lennerz JK, Corcoran RB, Heist RS, Russo AL, Parikh A, Borger DR, Blaszkowsky LS, Faris JE, Murphy JE, Azzoli CG, Roeland EJ, Goyal L, Allen J, Mullen JT, Ryan DP, Iafrate AJ, Klempner SJ, Clark JW, Hong TS. Revisiting MET: Clinical Characteristics and Treatment Outcomes of Patients with Locally Advanced or Metastatic, MET-Amplified Esophagogastric Cancers. Oncologist 2020; 25:e1691-e1700. [PMID: 32820577 DOI: 10.1634/theoncologist.2020-0274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/16/2020] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. PATIENTS AND METHODS Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. RESULTS We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). CONCLUSION MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. IMPLICATIONS FOR PRACTICE This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.
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Affiliation(s)
- Surendra Pal Chaudhary
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Eunice L Kwak
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Katie L Hwang
- Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jochen K Lennerz
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Ryan B Corcoran
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Rebecca S Heist
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Andrea L Russo
- Department of Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Aparna Parikh
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Darrell R Borger
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Lawrence S Blaszkowsky
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jason E Faris
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
- Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA
| | - Janet E Murphy
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher G Azzoli
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Eric J Roeland
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Lipika Goyal
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jill Allen
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - John T Mullen
- Department of Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - David P Ryan
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - A John Iafrate
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Samuel J Klempner
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Jeffrey W Clark
- Department of Medical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts, USA
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Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells 2020; 9:cells9092027. [PMID: 32899119 PMCID: PMC7563527 DOI: 10.3390/cells9092027] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 08/26/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.
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Huang L, Xie K, Li H, Wang R, Xu X, Chen K, Gu H, Fang J. Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody. Drug Des Devel Ther 2020; 14:3201-3214. [PMID: 32982167 PMCID: PMC7495354 DOI: 10.2147/dddt.s254117] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 07/17/2020] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing. MATERIALS AND METHODS A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb's effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody. RESULTS BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab. CONCLUSION c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.
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Affiliation(s)
- Lei Huang
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Kun Xie
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Hongwen Li
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Ruiqin Wang
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Xiaoqing Xu
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Kaiming Chen
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Hua Gu
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
| | - Jianmin Fang
- Laboratory of Molecular Medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai200092, People’s Republic of China
- Department of Neurology, Tongji Hospital, Tongji University, Shanghai, People’s Republic of China
- Biomedical Research Center, Tongji University Suzhou Institute, Suzhou, Jiangsu, People’s Republic of China
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De Herdt MJ, Koljenović S, van der Steen B, Willems SM, Wieringa MH, Nieboer D, Hardillo JA, Gruver AM, Zeng W, Liu L, Baatenburg de Jong RJ, Looijenga LHJ. A novel immunohistochemical scoring system reveals associations of C-terminal MET, ectodomain shedding, and loss of E-cadherin with poor prognosis in oral squamous cell carcinoma. Hum Pathol 2020; 104:42-53. [PMID: 32702402 DOI: 10.1016/j.humpath.2020.07.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 07/13/2020] [Indexed: 01/02/2023]
Abstract
Using tissue microarrays, it was shown that membranous C-terminal MET immunoreactivity and ectodomain (ECD) shedding are associated with poor prognosis in oral cancer. Seen the potential diagnostic value, extrapolation of these results to whole-tissue sections was investigated. Because MET orchestrates epithelial-to-mesenchymal transition (EMT), the results were benchmarked to loss of E-cadherin, a readout for EMT known to be associated with poor prognosis. C-terminal MET, N-terminal MET, and E-cadherin immunoreactivities were examined on formalin-fixed paraffin-embedded parallel sections of 203 oral cancers using antibody clones D1C2, A2H2-3, and NCH-38. Interantibody and intra-antibody relations were examined using a novel scoring system, nonparametric distribution, and median tests. Survival analyses were used to examine the prognostic value of the observed immunoreactivities. Assessment of the three clones revealed MET protein status (no, decoy, transmembranous C-terminal positive), ECD shedding, and EMT. For C-terminal MET-positive cancers, D1C2 immunoreactivity is independently associated with poor overall survival (hazard ratio [HR] = 2.40; 95% confidence interval [CI] = 1.25 to 4.61; and P = 0.008) and disease-free survival (HR = 1.83; 95% CI = 1.07-3.14; P = 0.027). For both survival measures, this is also the case for ECD shedding (43.4%, with HR = 2.30; 95% CI = 1.38 to 3.83; and P = 0.001 versus HR = 1.87; 95% CI = 1.19-2.92; P = 0.006) and loss of E-cadherin (55.3%, with HR = 2.21; 95% CI = 1.30 to 3.77; and P = 0.004 versus HR = 1.90; 95% CI = 1.20-3.01; P = 0.007). The developed scoring system accounts for MET protein status, ECD shedding, and EMT and is prognostically informative. These findings may contribute to development of companion diagnostics for MET-based targeted therapy.
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Affiliation(s)
- Maria J De Herdt
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center Rotterdam, Cancer Institute, 3015 GD, Rotterdam, the Netherlands.
| | - Senada Koljenović
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Cancer Institute, 3015 GD, Rotterdam, the Netherlands.
| | - Berdine van der Steen
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center Rotterdam, Cancer Institute, 3015 GD, Rotterdam, the Netherlands.
| | - Stefan M Willems
- Department of Pathology, University Medical Center Groningen, 9713 GZ, Groningen, the Netherlands.
| | - Marjan H Wieringa
- Department of Education, Office of Science, Elisabeth TweeSteden Ziekenhuis, 5022 GC, Tilburg, the Netherlands.
| | - Daan Nieboer
- Department of Public Health, Erasmus MC, University Medical Center Rotterdam, 3015 GD, Rotterdam, the Netherlands.
| | - Jose A Hardillo
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center Rotterdam, Cancer Institute, 3015 GD, Rotterdam, the Netherlands.
| | - Aaron M Gruver
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
| | - Wei Zeng
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
| | - Ling Liu
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46225, USA.
| | - Robert J Baatenburg de Jong
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center Rotterdam, Cancer Institute, 3015 GD, Rotterdam, the Netherlands.
| | - Leendert H J Looijenga
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Cancer Institute, 3015 GD, Rotterdam, the Netherlands; Princess Maxima Center for Pediatric Oncology, 3584 CS, Utrecht, the Netherlands.
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Tsujimoto H, Horiguchi H, Matsumoto Y, Takahata R, Shinomiya N, Yamori T, Miyazaki H, Ono S, Saitoh D, Kishi Y, Ueno H. A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway. J Clin Med 2020; 9:jcm9072074. [PMID: 32630328 PMCID: PMC7408644 DOI: 10.3390/jcm9072074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/22/2020] [Accepted: 06/29/2020] [Indexed: 02/04/2023] Open
Abstract
Background: Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. Methods: In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Results: Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Conclusions: Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.
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Affiliation(s)
- Hironori Tsujimoto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
- Correspondence: ; Tel.: +81-4-2995-1637
| | - Hiroyuki Horiguchi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
| | - Yusuke Matsumoto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
| | - Risa Takahata
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
| | - Nariyoshi Shinomiya
- Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan;
| | - Takao Yamori
- Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan;
| | - Hiromi Miyazaki
- Division of Traumatology, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.M.); (D.S.)
| | - Satoshi Ono
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
| | - Daizoh Saitoh
- Division of Traumatology, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.M.); (D.S.)
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan; (H.H.); (Y.M.); (R.T.); (S.O.); (Y.K.); (H.U.)
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Salgia R, Sattler M, Scheele J, Stroh C, Felip E. The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping. Cancer Treat Rev 2020; 87:102022. [DOI: 10.1016/j.ctrv.2020.102022] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/03/2020] [Accepted: 04/05/2020] [Indexed: 12/17/2022]
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The c-MET oncoprotein: Function, mechanisms of degradation and its targeting by novel anti-cancer agents. Biochim Biophys Acta Gen Subj 2020; 1864:129650. [PMID: 32522525 DOI: 10.1016/j.bbagen.2020.129650] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND The c-MET oncoprotein drives cancer progression in a variety of tumors through its signaling transduction pathways. This oncoprotein is also degraded by multiple mechanisms involving the lysosome, proteasome and cleavage by proteases. Targeting c-MET degradation pathways may result in effective therapeutic strategies. SCOPE OF REVIEW Since the discovery of oncogenic functions of c-MET, there has been a great deal of effort to develop anti-cancer drugs targeting this oncoprotein. Unexpectedly, novel di-2-pyridylketone thiosemicarbazones that demonstrate marked anti-tumor activity, down-regulate c-MET through their ability to bind intracellular iron and via mechanisms including, down-regulation of MET mRNA, enhanced lysosomal processing and increased metalloprotease-mediated cleavage. MAJOR CONCLUSIONS The c-MET oncoprotein regulation and degradation pathways are complex. However, with increasing understanding of its degradation mechanisms, there is also greater opportunities to therapeutically target these pathways. GENERAL SIGNIFICANCE Understanding the mechanisms of degradation of c-MET protein and its regulation could lead to novel therapeutics.
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Zarei B, Javidan Z, Fatemi E, Rahimi Jamnani F, Khatami S, Khalaj V. Targeting c-Met on gastric cancer cells through a fully human fab antibody isolated from a large naive phage antibody library. Daru 2020; 28:221-235. [PMID: 32193747 PMCID: PMC7238820 DOI: 10.1007/s40199-020-00334-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 02/14/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE The aberrant Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-Met) signaling pathway in various malignancies and its correlation with tumor invasion and poor prognosis has validated c-Met as a compelling therapeutic target. Up to now, several monoclonal antibodies and small molecule inhibitors targeting c-Met have been introduced with different outcomes, none are yet clinically approved. Toward the generation of novel fully human anti-c-Met molecules, we generated a large naïve Fab antibody library using phage display technology, which subsequently screened for novel Fabs against c-Met. METHODS A phage library, with a functional size of 5.5 × 1010 individual antibody clones, was prepared using standard protocols and screened for c-Met-specific Fabs by successive rounds of panning. A panel of Fabs targeting c-Met were isolated, from which four clones were selected and further characterized by DNA sequencing. The c-Met binding ability of our selected Fabs was evaluated by c-Met ELISA assay and flow cytometry techniques. RESULTS Among the confirmed anti-c-Met Fabs, clone C16, showed the highest affinity (Kaff: 0.3 × 109 M-1), and 63% binding to MKN45 cells (a human gastric adenocarcinoma cell-line) as compared to c-Met negative T47D cell-line (9.03%). CONCLUSION Together, our study presents a single-pot antibody library, as a valuable source for finding a range of antigen-specific Fab antibodies, and also, a fully human, high affinity and specific anti c-Met Fab antibody, C16, which has the potential of developing as a therapeutic or chemotherapeutic delivery agent for killing c-Met-positive tumor cells.
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Affiliation(s)
- Bahareh Zarei
- Medical Biotechnology Department, Biotechnology
Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Zahra Javidan
- Medical Biotechnology Department, Biotechnology
Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Elnaz Fatemi
- Medical Biotechnology Department, Biotechnology
Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Fatemeh Rahimi Jamnani
- Human Antibody Lab, Innovation Center, Pasteur Institute of Iran, Tehran, Iran
- Department of Mycobacteriology and Pulmonary Research,
Microbiology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Shohreh Khatami
- Biochemistry Department, Pasteur Institute of Iran, Tehran, Iran
| | - Vahid Khalaj
- Medical Biotechnology Department, Biotechnology
Research Center, Pasteur Institute of Iran, Tehran, Iran
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MET ectodomain shedding is associated with poor disease-free survival of patients diagnosed with oral squamous cell carcinoma. Mod Pathol 2020; 33:1015-1032. [PMID: 31857683 DOI: 10.1038/s41379-019-0426-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 01/07/2023]
Abstract
Ectodomain shedding unleashes the aggressive nature of the MET oncogene product. Using specific C- and N-terminal MET antibodies (D1C2 and A2H2-3), MET protein status (i.e., no MET, decoy MET, transmembranous C-terminal MET with or without the ectodomain) was investigated in oral squamous cell carcinoma. For the cancers showing transmembranous C-terminal MET, the impact of ectodomain shedding on prognosis was investigated. To examine ectodomain shedding, reduced lysates of oral squamous cell carcinoma cell lines were immunoblotted using D1C2 and an ELISA was performed on culture media using A2H2-3. In addition, reduced lysates of fresh frozen tissues of 30 oral squamous cell carcinoma were immunoblotted using D1C2 and immunohistochemistry was performed on corresponding formalin-fixed paraffin-embedded tissues using both antibodies on parallel sections. To examine MET protein status, differences between membranous D1C2 and A2H2-3 immunoreactivities were scored using parallel tissue microarray sections representing 156 oral squamous cell carcinoma. The prognostic value of ectodomain shedding was examined using Cox regression analysis for disease-free survival and overall survival. Ectodomain shedding was observed in all cell lines, 43% (n = 13) of fresh frozen and 50% (n = 15) of formalin-fixed paraffin-embedded cancers (27% overlap, n = 8). The tissue microarray showed no MET in 23% (n = 36), decoy MET in 9% (n = 14), and transmembranous C-terminal MET in 68% (n = 106) of examined cancers. Within the latter group, ectodomain shedding occurs in 36% (n = 38) of the cases and is independently associated with poor disease-free survival (HR = 2.41; 95% CI, 1.35-4.30 and P = 0.003)-though not overall survival (HR = 1.64; 95% CI, 0.92-2.94 and P = 0.095)-after correcting for factors known to influence survival. In conclusion, MET ectodomain shedding occurs in transmembranous C-terminal MET positive oral squamous cell carcinoma and is independently associated with disease-free survival. These findings might aid in designing companion diagnostics for targeted therapies directed against MET.
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Nie S, Yang G, Lu H. Current Molecular Targeted Agents for Advanced Gastric Cancer. Onco Targets Ther 2020; 13:4075-4088. [PMID: 32494161 PMCID: PMC7229784 DOI: 10.2147/ott.s246412] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/20/2020] [Indexed: 12/26/2022] Open
Abstract
Gastric cancer is the third leading cause of malignant tumor-related mortality worldwide. Traditional cytotoxic agents prolong the overall survival and progression-free survival of patients with advanced gastric cancer (AGC) compared to that with best supportive care. Due to the occurrence of serious adverse drug reactions that result in discontinued treatment, the survival benefit in AGC remains unsatisfactory. Systemic chemotherapy regimens have changed greatly, especially since the introduction of trastuzumab. Nevertheless, HER2 positivity is present in only approximately 20% of tumors. Due to the genetic heterogeneity and complexity of patients, there are many studies in progress that are exploring novel targeted drugs as an alternative to chemotherapy or adjuvant treatment in early-stage, progressive, and advanced gastric cancer. On the basis of the differences in gene expression profiles among patients, searching for specific and sensitive predictive biomarkers is important for identifying patients who will benefit from a specific targeted drug. With the development of targeted therapies and available chemotherapeutic drugs, there is no doubt that, over time, more patients will achieve better survival outcomes. Recently, immune checkpoint blockade has been well developed as a promising anticancer strategy. This review outlines the currently available information on clinically tested molecular targeted drugs and immune checkpoint inhibitors for AGC to provide support for decision-making in clinical practice.
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Affiliation(s)
- Shanshan Nie
- Center for Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Guoping Yang
- Center for Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
| | - Hongwei Lu
- Department of Cardiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
- Center for Experimental Medical Research, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China
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Sa JK, Kim SH, Lee JK, Cho HJ, Shin YJ, Shin H, Koo H, Kim D, Lee M, Kang W, Hong SH, Kim JY, Park YW, Song SW, Lee SJ, Joo KM, Nam DH. Identification of genomic and molecular traits that present therapeutic vulnerability to HGF-targeted therapy in glioblastoma. Neuro Oncol 2020; 21:222-233. [PMID: 29939324 DOI: 10.1093/neuonc/noy105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. METHODS To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. RESULTS We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. CONCLUSIONS Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.
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Affiliation(s)
- Jason K Sa
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Sung Heon Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin-Ku Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Hee Jin Cho
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Yong Jae Shin
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea.,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyemi Shin
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Harim Koo
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Donggeon Kim
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Mijeong Lee
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Wonyoung Kang
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
| | - Sung Hee Hong
- Hanmi Pharmaceutical Co. Ltd., Songpa-Gu, Seoul, Republic of Korea.,National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Jung Yong Kim
- National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Young-Whan Park
- National OncoVenture, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Seong-Won Song
- Yooyoung Pharmaceutical Co. Ltd., Guro-gu, Seoul, Republic of Korea
| | - Song-Jae Lee
- Yooyoung Pharmaceutical Co. Ltd., Guro-gu, Seoul, Republic of Korea
| | - Kyeung Min Joo
- Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Do-Hyun Nam
- Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Republic of Korea.,Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea.,Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Fu R, Jiang S, Li J, Chen H, Zhang X. Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression. Med Oncol 2020; 37:24. [PMID: 32166604 DOI: 10.1007/s12032-020-01350-4] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 02/25/2020] [Indexed: 12/11/2022]
Abstract
Lenvatinib is a long-awaited alternative to sorafenib for the first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to lenvatinib has also become a major obstacle to improving the prognosis of HCC patients. The underlying molecular mechanisms contributing to lenvatinib resistance in HCC are largely unknown. HGF/c-MET axis activation is related to tumor progression and several hallmarks of cancer and is considered as the key contributor to drug resistance. In the present study, we focused on the role of the HGF/c-MET axis in mediating lenvatinib resistance in HCC cells. We showed that HGF reduced the antiproliferative, proapoptotic, and anti-invasive effects of lenvatinib on HCC cells with high c-MET expression but did not significantly affect HCC cells with low c-MET expression. The c-MET inhibitor PHA-665752 rescued HCC cells from HGF-induced lenvatinib resistance. Furthermore, HGF/c-MET activated the downstream PI3K/AKT and MAPK/ERK pathways and promoted epithelial-mesenchymal transition (EMT) in HCC cells. Collectively, our results suggested that combining lenvatinib treatment with a c-MET inhibitor may improve its systemic therapeutic efficacy in HCC patients with high c-MET expression.
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Affiliation(s)
- Rongdang Fu
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-Sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, 510630, China
- Department of Hepatic Surgery, The Affiliated Foshan Hospital of Sun Yat-Sen University, Foshan, 528000, China
| | - Shaotao Jiang
- Department of HBP Surgery II, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China
| | - Jieyuan Li
- Department of Hepatic Surgery, The Affiliated Foshan Hospital of Sun Yat-Sen University, Foshan, 528000, China
| | - Huanwei Chen
- Department of Hepatic Surgery, The Affiliated Foshan Hospital of Sun Yat-Sen University, Foshan, 528000, China.
| | - Xiaohong Zhang
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-Sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, 510630, China.
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Yoo DK, Lee SR, Jung Y, Han H, Lee HK, Han J, Kim S, Chae J, Ryu T, Chung J. Machine Learning-Guided Prediction of Antigen-Reactive In Silico Clonotypes Based on Changes in Clonal Abundance through Bio-Panning. Biomolecules 2020; 10:E421. [PMID: 32182714 PMCID: PMC7175295 DOI: 10.3390/biom10030421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/04/2020] [Accepted: 03/06/2020] [Indexed: 02/07/2023] Open
Abstract
c-Met is a promising target in cancer therapy for its intrinsic oncogenic properties. However, there are currently no c-Met-specific inhibitors available in the clinic. Antibodies blocking the interaction with its only known ligand, hepatocyte growth factor, and/or inducing receptor internalization have been clinically tested. To explore other therapeutic antibody mechanisms like Fc-mediated effector function, bispecific T cell engagement, and chimeric antigen T cell receptors, a diverse panel of antibodies is essential. We prepared a chicken immune scFv library, performed four rounds of bio-panning, obtained 641 clones using a high-throughput clonal retrieval system (TrueRepertoireTM, TR), and found 149 antigen-reactive scFv clones. We also prepared phagemid DNA before the start of bio-panning (round 0) and, after each round of bio-panning (round 1-4), performed next-generation sequencing of these five sets of phagemid DNA, and identified 860,207 HCDR3 clonotypes and 443,292 LCDR3 clonotypes along with their clonal abundance data. We then established a TR data set consisting of antigen reactivity for scFv clones found in TR analysis and the clonal abundance of their HCDR3 and LCDR3 clonotypes in five sets of phagemid DNA. Using the TR data set, a random forest machine learning algorithm was trained to predict the binding properties of in silico HCDR3 and LCDR3 clonotypes. Subsequently, we synthesized 40 HCDR3 and 40 LCDR3 clonotypes predicted to be antigen reactive (AR) and constructed a phage-displayed scFv library called the AR library. In parallel, we also prepared an antigen non-reactive (NR) library using 10 HCDR3 and 10 LCDR3 clonotypes predicted to be NR. After a single round of bio-panning, we screened 96 randomly-selected phage clones from the AR library and found out 14 AR scFv clones consisting of 5 HCDR3 and 11 LCDR3 AR clonotypes. We also screened 96 randomly-selected phage clones from the NR library, but did not identify any AR clones. In summary, machine learning algorithms can provide a method for identifying AR antibodies, which allows for the characterization of diverse antibody libraries inaccessible by traditional methods.
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Affiliation(s)
- Duck Kyun Yoo
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seung Ryul Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Yushin Jung
- Celemics, Inc., 131 Gasandigital 1-ro, Geumcheon-gu, Seoul 08506, Korea
| | - Haejun Han
- Celemics, Inc., 131 Gasandigital 1-ro, Geumcheon-gu, Seoul 08506, Korea
| | - Hwa Kyoung Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jerome Han
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Soohyun Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jisu Chae
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Taehoon Ryu
- Celemics, Inc., 131 Gasandigital 1-ro, Geumcheon-gu, Seoul 08506, Korea
| | - Junho Chung
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
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Bispecific Antibodies and Antibody-Drug Conjugates for Cancer Therapy: Technological Considerations. Biomolecules 2020; 10:biom10030360. [PMID: 32111076 PMCID: PMC7175114 DOI: 10.3390/biom10030360] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/20/2020] [Accepted: 02/23/2020] [Indexed: 01/07/2023] Open
Abstract
The ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field. In recent years, traditional immunoglobulin antibodies have been further engineered for better efficacy and safety, and technological developments in the field enabled the design and production of engineered antibodies capable of mediating therapeutic functions hitherto unattainable by conventional antibody formats. Representative of this newer generation of therapeutic antibody formats are bispecific antibodies and antibody–drug conjugates, each with several approved drugs and dozens more in the clinical development phase. In this review, the technological principles and challenges of bispecific antibodies and antibody–drug conjugates are discussed, with emphasis on clinically validated formats but also including recent developments in the fields, many of which are expected to significantly augment the current therapeutic arsenal against cancer and other diseases with unmet medical needs.
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Hoffmann K, Nagel AJ, Tanabe K, Fuchs J, Dehlke K, Ghamarnejad O, Lemekhova A, Mehrabi A. Markers of liver regeneration-the role of growth factors and cytokines: a systematic review. BMC Surg 2020; 20:31. [PMID: 32050952 PMCID: PMC7017496 DOI: 10.1186/s12893-019-0664-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.
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Affiliation(s)
- Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany.
| | - Alexander Johannes Nagel
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Kazukata Tanabe
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | | | - Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Anastasia Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
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Moosavi F, Giovannetti E, Saso L, Firuzi O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit Rev Clin Lab Sci 2019; 56:533-566. [PMID: 31512514 DOI: 10.1080/10408363.2019.1653821] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 07/13/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022]
Abstract
Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.
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Affiliation(s)
- Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc) , Amsterdam , The Netherlands
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza Onlus , Pisa , Italy
| | - Luciano Saso
- Department of Physiology and Pharmacology, "Vittorio Erspamer," Sapienza University , Rome , Italy
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
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50
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EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming. Nat Commun 2019; 10:5033. [PMID: 31695034 PMCID: PMC6834558 DOI: 10.1038/s41467-019-13034-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 10/14/2019] [Indexed: 12/13/2022] Open
Abstract
The molecular mechanisms driving metastatic progression in triple-negative breast cancer (TNBC) patients are poorly understood. In this study, we demonstrate that epidermal growth factor-like 9 (EGFL9) is significantly upregulated in basal-like breast cancer cells and associated with metastatic progression in breast tumor samples. Functionally, EGFL9 is both necessary and sufficient to enhance cancer cell migration and invasion, as well as distant metastasis. Mechanistically, we demonstrate that EGFL9 binds cMET, activating cMET-mediated downstream signaling. EGFL9 and cMET co-localize at both the cell membrane and within the mitochondria. We further identify an interaction between EGFL9 and the cytochrome c oxidase (COX) assembly factor COA3. Consequently, EGFL9 regulates COX activity and modulates cell metabolism, promoting a Warburg-like metabolic phenotype. Finally, we show that combined pharmacological inhibition of cMET and glycolysis reverses EGFL9-driven stemness. Our results identify EGFL9 as a therapeutic target for combating metastatic progression in TNBC. Triple-negative breast cancer is an aggressive form of the disease. Here, the authors identify EGFL9 as a mediator of metastasis in TNBC through interactions with cMET.
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