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Baez-Navarro X, Groenendijk FH, Oudijk L, von der Thüsen J, Fusco N, Curigliano G, van Deurzen CHM. HER2-low across solid tumours: different incidences and definitions. Pathology 2025; 57:403-414. [PMID: 40221332 DOI: 10.1016/j.pathol.2025.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/22/2025] [Accepted: 02/10/2025] [Indexed: 04/14/2025]
Abstract
Antibody-drug conjugates, particularly trastuzumab deruxtecan (T-DXd), have emerged as effective therapies for various solid tumours. Clinical trials show that T-DXd improves survival in both HER2-positive and HER2-low breast cancer patients. Additionally, it improves survival in HER2-positive gastro-oesophageal cancer and elicits objective responses in HER2-low tumours. Responses have also been noted in lung and gynaecological cancers with HER2 expression, although subgroup analyses for HER2-low cases are lacking. This review assesses HER2 protein expression levels and gene amplification across solid tumours where T-DXd shows potential benefits. We focus on the accuracy and limitations of HER2 testing methods, particularly for identifying HER2-low cancer. A semi-systematic approach was employed, searching EMBASE, Medline, Cochrane, and PubMed databases. We calculated median incidences of HER2-positive, HER2-low, and HER2-0 by immunohistochemistry (IHC), and HER2 amplification by in situ hybridisation (ISH). A total of 144 studies were included, covering breast (n=57), gastro-oesophageal (n=33), lung (n=17), gynaecological (n=24), and various other carcinomas (n=13). The median incidences of HER2-low were 52%, 16%, 58%, and 17% in breast, gastro-oesophageal, endometrial, and ovarian cancers, respectively, with unknown incidences in lung and cervical cancers. Factors influencing HER2-low detection include tumour heterogeneity, antibody clones, observer variability, and lack of validated scoring criteria. Given the significant proportion of HER2-low cases, many patients could benefit from T-DXd, but limitations in detection accuracy necessitate further research and standardisation in diagnostic methods and criteria to advance the clinical utility of T-DXd for HER2-low tumours.
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Affiliation(s)
- Ximena Baez-Navarro
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
| | | | - Lindsey Oudijk
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jan von der Thüsen
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy
| | - Giuseppe Curigliano
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy
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Park S, Oh AY, Hong BS, Shin YJ, Jang H, Seo H, Kang SM, Woo TG, Park HP, Jeong J, Kim HJ, Kim BH, Kwon Y, Park BJ. The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200875. [PMID: 39351074 PMCID: PMC11439892 DOI: 10.1016/j.omton.2024.200875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/16/2024] [Accepted: 09/05/2024] [Indexed: 10/04/2024]
Abstract
Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).
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Affiliation(s)
- Soyoung Park
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Ah-Young Oh
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Byung-Su Hong
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Yun-Jeong Shin
- Department of Agricultural Biotechnology, College of Agricultural Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyewon Jang
- Department of Agricultural Biotechnology, College of Agricultural Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyunghwan Seo
- Department of Agricultural Biotechnology, College of Agricultural Science, Seoul National University, Seoul 08826, Republic of Korea
| | - So-mi Kang
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Tae-Gyun Woo
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Hyo-Pin Park
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Jiwon Jeong
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Hye-Ju Kim
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
| | - Bae-Hoon Kim
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
- Research Institute of PRG S&Tech, PRG S&Tech Co., Ltd., Busan 46274, Republic of Korea
| | - Yonghoon Kwon
- Department of Agricultural Biotechnology, College of Agricultural Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Bum-Joon Park
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea
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Pendleton KE, Wang K, Echeverria GV. Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations. Front Cell Dev Biol 2023; 11:1254313. [PMID: 37779896 PMCID: PMC10534013 DOI: 10.3389/fcell.2023.1254313] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Deregulation of tumor cell metabolism is widely recognized as a "hallmark of cancer." Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging "hallmark of cancer." Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic (i.e., reversible) and permanent (i.e., stable) metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients.
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Affiliation(s)
- Katherine E. Pendleton
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
| | - Karen Wang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
- Department of BioSciences, Rice University, Houston, TX, United States
| | - Gloria V. Echeverria
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, United States
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
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Abu Al Karsaneh O, Al Anber A, ALQudah M, Al-Mustafa S, AlMa'aitah H, Sughayer M. Prevalence and clinicopathological associations of HER2 expression in non-small cell lung cancer: a retrospective study in Jordanian patients. Diagn Pathol 2023; 18:75. [PMID: 37340403 DOI: 10.1186/s13000-023-01364-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/12/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2), a promising therapeutic target, can be mutated, amplified, or overexpressed in different malignancies, including non-small cell lung cancer (NSCLC). Although these alterations showed adverse prognostic effects in many cancers, their clinical significance in NSCLC is controversial. This study primarily assessed the prevalence of HER2 protein expression in NSCLC among Jordanian patients. In addition, the possible association between HER2 protein expression and clinicopathological variables was evaluated. METHODS A total of 100 surgically resected NSCLC cases treated at King Hussein Cancer Center (KHCC) between 2009 and 2021 were examined for HER2 protein expression using immunohistochemistry (IHC). The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for breast cancer were applied to interpret the results with a final score ranging from 0 to 3+, considering a score of 3 + as overexpression. Additionally, a separate subset of patients was tested for HER2 gene mutation. Fisher's exact test was used to assess the association between HER2 scores and the other variables. Kaplan-Meier method was used to calculate survival. RESULTS Of the 100 cases, Her2 overexpression (score 3+) was detected in 2 cases (2%), score 2 + in 10 cases (10%), score 1 + in 12 cases (12%), and score 0 in 76 cases (76%). The two positive cases were one adenocarcinoma and one squamous cell carcinoma; both patients were elderly male smokers. No significant association was identified between Her2 expression and age, gender, smoking, histological subtype, grade, stage, tumor size, and lymph node status. Our findings also showed no association between Her2 expression and survival; however, advanced tumor stages and positive lymph node metastasis were significantly associated with poor overall survival. All cases tested for the Her2 mutation were negative. CONCLUSIONS Her2 overexpression is uncommon in NSCLC among the Jordanian population. However, when the same scoring criteria are used, the rates are similar to other results found in Asian cohorts. Due to our study's relatively small sample size, a larger one is required to investigate the prognostic value and the molecular associations between the different Her2 alterations.
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Affiliation(s)
- Ola Abu Al Karsaneh
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Arwa Al Anber
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Mohammad ALQudah
- Department of Microbiology, Pathology and Forensic Medicine, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
| | - Sahar Al-Mustafa
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Hussien AlMa'aitah
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Maher Sughayer
- Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan.
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Yun KM, Bazhenova L. Metastatic HER2-amplified non-small-cell lung cancer treated with trastuzumab deruxtecan. BMJ Case Rep 2023; 16:e253260. [PMID: 37156567 PMCID: PMC10173996 DOI: 10.1136/bcr-2022-253260] [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: 04/26/2023] [Indexed: 05/10/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) alterations can occur as gene mutations, gene amplification or protein overexpression. DESTINY-Lung01 and DESTINY-Lung02 demonstrated the efficacy of trastuzumab deruxtecan in the subsequent line setting in patients with unresectable or metastatic HER2-mutated non-small-cell lung cancer (NSCLC). Trastuzumab deruxtecan has not been studied in select patients with HER2-amplified NSCLC. Here, we present the first reported case of metastatic HER2-amplified NSCLC treated with trastuzumab deruxtecan with a durable response to therapy.
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Affiliation(s)
- Karen M Yun
- Division of Hematology-Oncology, Moores Cancer Center at UC San Diego Health, La Jolla, California, USA
| | - Lyudmila Bazhenova
- Division of Hematology-Oncology, Moores Cancer Center at UC San Diego Health, La Jolla, California, USA
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Vtorushin SV, Krakhmal NV, Zavalishina LE, Kuznetsova OA, Moskvina LV, Frank GA. [Assessment of HER2 status of carcinomas of various localizations]. Arkh Patol 2023; 85:31-46. [PMID: 38010637 DOI: 10.17116/patol20238506131] [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] [Indexed: 11/29/2023]
Abstract
A detailed description of the methodological aspects of the evaluation of HER2-status in carcinomas of such localizations as the mammary gland, pancreas, salivary glands, stomach, colon, endometrium, bladder, lungs is presented. Approaches and criteria for assessing HER2 status from methodological and clinical points of view are analyzed. The data are systematized in tables for use in practical diagnostic work.
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Affiliation(s)
- S V Vtorushin
- Siberian State Medical University, Tomsk, Russia
- Cancer Research Institute of Tomsk National Research Medical Center, Tomsk, Russia
| | - N V Krakhmal
- Siberian State Medical University, Tomsk, Russia
- Cancer Research Institute of Tomsk National Research Medical Center, Tomsk, Russia
| | - L E Zavalishina
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - O A Kuznetsova
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - L V Moskvina
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | - G A Frank
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
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Tan AC, Saw SP, Chen J, Lai GG, Oo HN, Takano A, Lau DP, Yeong JP, Tan GS, Lim KH, Skanderup AJ, Chan JW, Teh YL, Rajasekaran T, Jain A, Tan WL, Ng QS, Kanesvaran R, Lim WT, Ang MK, Tan DS. Clinical and Genomic Features of HER2 Exon 20 Insertion Mutations and Characterization of HER2 Expression by Immunohistochemistry in East Asian Non–Small-Cell Lung Cancer. JCO Precis Oncol 2022; 6:e2200278. [DOI: 10.1200/po.22.00278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
PURPOSE HER2-altered non–small-cell lung cancer (NSCLC) represents a diverse subgroup, including mutations, amplifications, and overexpression. However, HER2 exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of HER2-altered NSCLC in an Asian tertiary cancer center. METHODS We identified patients with HER2-mutated NSCLC in our institutional database, collating clinicopathological features and treatment outcomes. The genomic landscape of human epidermal growth factor receptor 2 ( HER2)–mutated NSCLC was further evaluated using whole-exome sequencing (WES) data from combined local and publicly available data sets. HER2 amplification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data. RESULTS Among 1,252 patients with consecutive lung adenocarcinoma undergoing routine next-generation sequencing, the prevalence of HER2 mutations was 3.1%—exon 20 insertion mutations comprised 2.7%. We examined the clinicopathological features in 55 patients with HER2-mutated NSCLC comprising 40 exon 20 insertion and 15 nonexon 20 insertion mutations. The most common exon 20 insertion mutation was HER2Y772_A775dup in 30 (75%), followed by HER2G776delinsVC in five patients (13%). There were limited responses to HER2-directed therapies apart from trastuzumab-deruxtecan, and no responses were seen with immunotherapy monotherapy. Evaluating the genomics features of HER2 exon 20 insertion mutations using WES data revealed low tumor mutational burden (TMB), low incidence of cancer driver comutations, and a predominance of aging mutational signature—similar to EGFR-mutated tumors. In contrast, uncommon (or nonexon 20 insertion) HER2-mutated tumors resembled EGFR wild-type tumors with higher TMB, higher frequency of cancer driver comutations, and greater presence of smoking and APOBEC mutational signature. Finally, in evaluating HER2 immunohistochemistry in all lung adenocarcinoma, there was significant discordance comparing different scoring systems and poor correlation with HER2 RNA expression and HER2 amplification. CONCLUSION The incidence of HER2 mutations is 3.1% in East Asian nonsquamous NSCLC. HER2 exon 20 insertion–mutated tumors appear genomically distinct from uncommon (nonexon 20 insertion) HER2 mutations, the latter demonstrating higher TMB, co-occurring drivers, and predominant nonaging mutational signature. The therapeutic implications of the genomic and clinical features of HER2-mutated NSCLC warrant further investigation.
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Affiliation(s)
- Aaron C. Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Stephanie P.L. Saw
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Jianbin Chen
- Genome Institute of Singapore, Singapore, Singapore
| | - Gillianne G.Y. Lai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Hlaing Nwe Oo
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Angela Takano
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Dawn P.X. Lau
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joe P.S. Yeong
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Gek San Tan
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Kiat Hon Lim
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | | | - Johan W.K. Chan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Yi Lin Teh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Tanujaa Rajasekaran
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Amit Jain
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Wan Ling Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Quan Sing Ng
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Ravindran Kanesvaran
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Wan-Teck Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Mei-Kim Ang
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Daniel S.W. Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
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Mutation Profiles of Ovarian Seromucinous Borderline Tumors in Japanese Patients. Curr Oncol 2022; 29:3658-3667. [PMID: 35621684 PMCID: PMC9139622 DOI: 10.3390/curroncol29050294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/22/2022] [Accepted: 04/29/2022] [Indexed: 11/17/2022] Open
Abstract
Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations (KRAS, BRAF, PIK3CA, and ERBB2) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A. ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.
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Consensus for HER2 alterations testing in non-small-cell lung cancer. ESMO Open 2022; 7:100395. [PMID: 35149428 PMCID: PMC8844658 DOI: 10.1016/j.esmoop.2022.100395] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/27/2021] [Accepted: 01/06/2022] [Indexed: 02/08/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Meanwhile, several HER2-targeted drugs, such as T-DXd, neratinib, afatinib, poziotinib and pyrotinib, have been evaluated in patients with advanced NSCLC, with several of them demonstrating clinical benefit. Therefore, identifying HER2 alterations is pivotal for NSCLC patients to benefit from these targeted therapies. Recent guidelines on HER2 testing were developed for breast and gastric cancer, however, and have not been fully established for NSCLC. The expert group here reached a consensus on HER2 alteration testing in NSCLC with the focus on clinicopathologic characteristics, therapies, detection methods and diagnostic criteria for HER2-altered NSCLC patients. We hope this consensus could improve the clinical management of NSCLC patients with HER2 alterations.
Human epidermal growth factor receptor 2 (HER2) alterations lead to poor prognosis in non-small-cell lung cancer (NSCLC). Identifying HER2 alterations is pivotal to guide the anti-HER2-targeted therapies in NSCLC. The requirements for HER2 mutation, amplification or expression testing are distinct in NSCLC. This consensus fills the gap in the criteria for HER2 alteration testing in NSCLC.
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10
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Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open 2021; 6:100260. [PMID: 34479034 PMCID: PMC8414039 DOI: 10.1016/j.esmoop.2021.100260] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 12/16/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in HER2-mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone [median progression-free survival (PFS) 6.1 versus 7 months, respectively] and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in HER2-mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody–drug conjugates (ADCs) ado-trastuzumab–emtansine and trastuzumab–deruxtecan in patients with HER2-mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.
Activation of Her2 in NSCLC occurs via gene mutation, amplification or protein overexpression. Selective Her2 TKIs like poziotinib and pyrotinib induced responses in up to 44% of pre-treated Her2-mutant NSCLC patients. ADCs trastuzumab–emtansine and trastuzumab–deruxtecan showed impressive response rates in 62% of Her2-mutant NSCLC patients. Ongoing studies evaluating combination strategies may help improve the therapeutic landscape in Her2-dependent NSCLC.
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Affiliation(s)
- M Riudavets
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | - I Sullivan
- Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - P Abdayem
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | - D Planchard
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France.
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11
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Lim YX, Lin H, Chu T, Lim YP. WBP2 promotes BTRC mRNA stability to drive migration and invasion in triple-negative breast cancer via NF-κB activation. Mol Oncol 2021; 16:422-446. [PMID: 34197030 PMCID: PMC8763649 DOI: 10.1002/1878-0261.13048] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/04/2021] [Accepted: 06/28/2021] [Indexed: 01/23/2023] Open
Abstract
WW‐domain‐binding protein 2 (WBP2) is an oncogene that drives breast carcinogenesis through regulating Wnt, estrogen receptor (ER), and Hippo signaling. Recent studies have identified neoteric modes of action of WBP2 other than its widely recognized function as a transcriptional coactivator. Here, we identified a previously unexplored role of WBP2 in inflammatory signaling in breast cancer via an integrated proteogenomic analysis of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) dataset. WBP2 was shown to enhance the migration and invasion in triple‐negative breast cancer (TNBC) cells especially under tumor necrosis factor alpha (TNF‐α) stimulation. Molecularly, WBP2 potentiates TNF‐α‐induced nuclear factor kappa B (NF‐κB) transcriptional activity and nuclear localization through aggrandizing ubiquitin‐mediated proteasomal degradation of its upstream inhibitor, NF‐κB inhibitor alpha (NFKBIA; also known as IκBα). We further demonstrate that WBP2 induces mRNA stability of beta‐transducin repeat‐containing E3 ubiquitin protein ligase (BTRC), which targets IκBα for ubiquitination and degradation. Disruption of IκBα rescued the impaired migratory and invasive phenotypes in WBP2‐silenced cells, while loss of BTRC ameliorated WBP2‐driven migration and invasion. Clinically, the WBP2‐BTRC‐IκBα signaling axis correlates with poorer prognosis in breast cancer patients. Our findings reveal a pivotal mechanism of WBP2 in modulating BTRC‐IκBα‐NF‐κB pathway to promote TNBC aggressiveness.
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Affiliation(s)
- Yvonne Xinyi Lim
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Hexian Lin
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Tinghine Chu
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Department of Biomedical Informatics, Yong Loo Lin School of Medicine, National University Health System, Singapore City, Singapore
| | - Yoon Pin Lim
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,National University Cancer Institute, Singapore City, Singapore
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12
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Zhao J, Xia Y. Targeting HER2 Alterations in Non–Small-Cell Lung Cancer: A Comprehensive Review. JCO Precis Oncol 2020; 4:411-425. [PMID: 35050738 DOI: 10.1200/po.19.00333] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
PURPOSE HER2 is a critical gene that drives various solid tumors in addition to those of breast cancer. For example, HER2 plays a role in non–small-cell lung cancer (NSCLC). Overexpression, amplification, and point mutations in HER2 have been described in patients with NSCLC; however, the potential roles of these alterations remain unclear. METHODS We summarize the evidence regarding the distinct impacts of different HER2 aberrations on antitumor agents. Also, we update the therapeutic efficacy of HER2-targeted agents, including anti-HER2 antibodies, antibody-drug conjugates, and small-molecule tyrosine kinase inhibitors, tested in HER2-aberrant NSCLC. RESULTS Although these drugs are not yet standard treatments, certain patients may benefit from these therapies. In this review, we aim to provide an improved understanding of HER2 aberrations in NSCLC, including NSCLC biology and the impacts of each aberration on prognosis and standard treatment. We also highlight the potential of novel anti-HER2 therapies approved by regulatory bodies and those in clinical development. CONCLUSION Compared with HER2 amplification or overexpression, HER2 mutations, especially HER2 exon 20 mutations, are emerging as the most clear targetable driver for HER2-directed therapies in lung cancer. De novo and inducible HER2 pathway activation need to be differentially managed. Further investigations with new strategies are needed.
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Affiliation(s)
- Jing Zhao
- Department of Medical Oncology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yang Xia
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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13
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Sankar K, Gadgeel SM, Qin A. Molecular therapeutic targets in non-small cell lung cancer. Expert Rev Anticancer Ther 2020; 20:647-661. [PMID: 32580596 DOI: 10.1080/14737140.2020.1787156] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Several targetable genetic alterations have been identified in non-small cell lung cancers (NSCLC) and drugs targeting these alterations have been approved for the management of advanced NSCLC patients. Driver mutations with emerging clinical trial data include EGFR exon 20 insertion mutations, MET amplification, KRAS G12 C point mutations, RET rearrangements, HER2 amplification and mutations, and FGFR amplification and translocations. AREAS COVERED We reviewed English-language articles indexed in Medline and PubMed up to the 1st of June 2020. In addition, the proceedings of major conferences were reviewed for relevant abstracts. We report data published regarding targeted therapies which are currently approved and for those which are emerging in advanced or metastatic NSCLC. EXPERT REVIEW While these drugs have been shown to be efficacious and tolerable, resistance almost always develops. Though next-generation tyrosine kinase inhibitors (TKIs) have been developed, the appropriate sequencing of these drugs is not clear. Evaluating combination therapies to prevent or delay the onset of resistance and understanding mechanisms of resistance are critical areas of emerging research.
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Affiliation(s)
| | | | - Angel Qin
- University of Michigan , Ann Arbor, MI, USA
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14
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Affiliation(s)
- S Ekman
- Department of Oncology-Pathology, Karolinska Institutet/Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden.
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15
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Jeon HJ, Choi BBR, Park KH, Hwang DS, Kim UK, Kim GC. Induction of Melanoma Cell-Selective Apoptosis Using Anti-HER2 Antibody-Conjugated Gold Nanoparticles. Yonsei Med J 2019; 60:509-516. [PMID: 31124333 PMCID: PMC6536400 DOI: 10.3349/ymj.2019.60.6.509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/07/2019] [Accepted: 04/05/2019] [Indexed: 02/02/2023] Open
Abstract
PURPOSE This study was conducted to verify the induction and mechanism of selective apoptosis in G361 melanoma cells using anti-HER2 antibody-conjugated gold nanoparticles (GNP-HER2). MATERIALS AND METHODS Following GNP-HER2 treatment of G361 cells, cell cycle arrest and apoptosis were measured by WST-1 assay, Hemacolor staining, Hoechst staining, immunofluorescence staining, fluorescence-activated cell sorting analysis, and Western blotting. RESULTS G361 cells treated with GNP-HER2 showed condensation of nuclei, which is an apoptotic phenomenon, and translocation of apoptosis-inducing factor and cytochrome c from mitochondria into the nucleus and cytoplasm, respectively. Increases in BAX in cells undergoing apoptosis, activation of caspase-3 and -9, and fragmentation of poly (ADP-ribose) polymerase and DNA fragmentation factor 45 (inhibitor of caspase-activated DNase) were observed upon GNP-HER2 treatment. Following GNP-HER2 treatment, an increase of cells in sub-G1 phase, which is a signal of cell apoptosis, was observed. This resulted in the down-regulation of cyclin A, cyclin D1, cyclin E, cdk2, cdk4, and cdc2 and the up-regulation of p21. Thus, GNP-HER2 treatment was confirmed to induce the cessation of cell cycle progression. Also, decreases in phospho-focal adhesion kinase and phospho-human epidermal growth factor receptor, which activate cellular focal adhesion, and decreases in phospho-paxillin, which stimulates the disassembly of filamentous actin, were observed. Reduced cell adhesion and disassembly of the intracellular structure indicated cell deactivation. CONCLUSION GNP-HER2 can selectively kill G361 melanoma cells without affecting normal cells. The mechanism of G361 cell death upon treatment with GNP-HER2 was apoptosis accompanied by activation of caspases.
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Affiliation(s)
- Hyeon Jun Jeon
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Byul Bo Ra Choi
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Yangsan, Korea
- Feagle Co., Ltd., Yangsan, Korea
| | - Kwang Ha Park
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Dae Seok Hwang
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Uk Kyu Kim
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea.
| | - Gyoo Cheon Kim
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Yangsan, Korea.
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16
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Concordance analysis between HER2 immunohistochemistry and in situ hybridization in non-small cell lung cancer. Int J Biol Markers 2018; 33:49-54. [PMID: 28478639 DOI: 10.5301/ijbm.5000271] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE This study aimed to elucidate the concordance between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and in situ hybridization (ISH) and the diagnostic accuracy of HER2 IHC in non-small cell lung cancer (NSCLC) through a meta-analysis and diagnostic test accuracy review. METHODS Seven eligible studies and 1,217 patients with NSCLC were included in the review. The concordance between HER2 IHC and ISH was analyzed. To confirm the diagnostic accuracy of HER2 IHC, the sensitivity and specificity were analyzed and the area under the curve (AUC) in the summary receiver operating characteristic (SROC) curve was calculated. RESULTS The concordance rate between HER2 IHC and ISH was 0.795 (95% confidence interval [CI] 0.534-0.929). In the HER2 IHC-negative (score 0/1+) subgroup, the concordance rate was 0.975 (95% CI 0.854-0.996). The concordance rates of the HER2 IHC score 2+ and 3+ subgroups were 0.091 (95% CI 0.039-0.197) and 0.665 (95% CI 0.446-0.830), respectively. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.67 (95% CI 0.54-0.78) and 0.89 (95% CI 0.87-0.91), respectively. The AUC in the SROC curve was 0.891 and the diagnostic odds ratio was 16.99 (95% CI 5.08-56.76). CONCLUSIONS HER2 IHC was largely in agreement with ISH in cases of HER2 IHC score 0/1+. Because the concordance rates of HER2 IHC score 2/3+ cases were lower than that of HER2 IHC score 0/1+ cases, further studies for detailed analysis criteria for HER2 IHC score 2+ or 3+ are required.
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17
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Scrima M, Zito Marino F, Oliveira DM, Marinaro C, La Mantia E, Rocco G, De Marco C, Malanga D, De Rosa N, Rizzuto A, Botti G, Franco R, Zoppoli P, Viglietto G. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients. J Cancer 2017; 8:227-239. [PMID: 28243327 PMCID: PMC5327372 DOI: 10.7150/jca.17093] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 10/17/2016] [Indexed: 12/30/2022] Open
Abstract
Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.
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Affiliation(s)
- Marianna Scrima
- Biogem scarl, Institute of Genetic Research, Ariano Irpino (AV), Italy.; Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Federica Zito Marino
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Duarte Mendes Oliveira
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Cinzia Marinaro
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Elvira La Mantia
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Gaetano Rocco
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Carmela De Marco
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Donatella Malanga
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | | | - Antonia Rizzuto
- Department of Medical and Surgical Sciences, University "Magna Graecia" Medical School, Catanzaro, Italy
| | - Gerardo Botti
- Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | | | - Pietro Zoppoli
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, University "Magna Graecia", Catanzaro, Italy
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18
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Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. Sci Rep 2016; 6:39557. [PMID: 28008968 PMCID: PMC5180104 DOI: 10.1038/srep39557] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 11/24/2016] [Indexed: 01/03/2023] Open
Abstract
HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.
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19
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Li G, Gao Y, Cui Y, Zhang T, Cui R, Jiang Y, Shi J. Overexpression of CD44 is associated with the occurrence and migration of non-small cell lung cancer. Mol Med Rep 2016; 14:3159-67. [PMID: 27573351 PMCID: PMC5042784 DOI: 10.3892/mmr.2016.5636] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 07/07/2016] [Indexed: 11/17/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a potentially fatal disease and the incidence is increasing annually. In order to diagnose and treat NSCLC effectively, greater understanding of its molecular mechanism is required. In the present study, 36 NSCLC tissues and 10 normal tissues were selected. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the CD44 mRNA expression level in NSCLC tissue and DNA sequencing was performed to further verify the CD44 expression level. Differentially expressed genes between tumor tissues and controls were determined by DNA sequencing and the Gene_act_net between CD44 and its associated genes was constructed. Gene Ontology (GO) term enrichment analysis of the differentially expressed genes was performed by the Biological Networks Gene Ontology tool. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed based on the Expression Analysis Systematic Explorer test applied in the Database for Annotation, Visualization and Integrated Discovery. RT-qPCR results showed that CD34 was overexpressed in 21 of the 36 NSCLC tissues (58.3%). The Gene_act_net indicated that there were 20 differentially expressed genes with 17 upregulated and 3 downregulated. Among them, CD44, MET, ERBB2, EGFR, AKT1, IQGAP1 and STAT3 were associated with the occurrence and migration of NSCLC. In KEGG pathway analysis, extracellular matrix-receptor interaction and hematopoietic cell lineage pathways were the most affected by overexpressed CD44; and thus may be important in the development and migration of NSCLC. In conclusion, CD44 was overexpressed in NSCLC and the overexpression was associated with the occurrence of NSCLC and migration of NSCLC cells.
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Affiliation(s)
- Guanghu Li
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yufei Gao
- Department of Neurosurgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yongsheng Cui
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Tao Zhang
- Department of Gastrointestinal Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Rui Cui
- Department of Laboratory Medicine Center, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yang Jiang
- Department of Colorectal Surgery, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Jingwei Shi
- Department of Laboratory Medicine Center, China‑Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
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20
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Arriola E, Taus &A, Casadevall D. Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wild-type non-small cell lung cancer? World J Clin Oncol 2015; 6:45-56. [PMID: 26266101 PMCID: PMC4530378 DOI: 10.5306/wjco.v6.i4.45] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 05/08/2015] [Accepted: 06/04/2015] [Indexed: 02/06/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a world-wide annual incidence of around 1.3 million. The majority of patients are diagnosed with advanced disease and survival remains poor. However, relevant advances have occurred in recent years through the identification of biomarkers that predict for benefit of therapeutic agents. This is exemplified by the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the treatment of EGFR mutant patients. These drugs have also shown efficacy in unselected populations but this point remains controversial. Here we have reviewed the clinical data that demonstrate a small but consistent subgroup of EGFR wild-type patients with NSCLC that obtain a clinical benefit from these drugs. Moreover, we review the biological rationale that may explain this benefit observed in the clinical setting.
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Kobyakov DS, Avdalyan AM, Klimachev VV, Lazarev AF, Lushnikova EL, Nepomnyaschikh LM. [Non-small cell lung cancer: HER2 oncogene status]. Arkh Patol 2015; 77:3-9. [PMID: 26027392 DOI: 10.17116/patol20157723-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE to study HER2 protein and HER2 gene, their heterogeneity in non-small cell lung cancer. MATERIAL AND METHODS 218 intraoperative non-small cell lung samples were examined using tissue matrix methods. HER2 protein was determined by immunohistochemistry (clone 4B5, <<Ventana>> and HER2 gene and CEP1 7 were evaluated by in situ hybridization (SISH, <<Ventana>>). RESULTS Positive and indefinite statuses were found in 59 (27%) and 47 (22%) cases, respectively; intratumor heterogeneity was detected in 32 (30%) cases. Amplification of the HER-2 gene was found in 12 (6%) cases; that of the HER2 gene along with an increase in CEPI 7 was observed in 7 (3%) cases; elevated CEP1 7 levels were seen in 19 (9%) cases. Intratumor heterogeneity of HER2 gene amplification was not found; however, one case of adenocarcinoma showed high-level HER2 gene amplification in the gland-like areas and low-level HER2 gene amplification in the solid areas. HER2-positive status and amplification were more common in adenocarcinoma than in squamous cell carcinoma (p<0.001). There was a moderate correlation between HER2 immunohistochemical status and amplification (r=0.38; p<0.001). CONCLUSION Thus, in non-small cell lung cancer, there is an elevated HER2 protein level and, well less frequently, altered activity in the HER2 gene (amplification) as a cause of enhanced protein synthesis.
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Affiliation(s)
| | - A M Avdalyan
- Laboratory of Molecular Diagnosis, Altai Branch, N.N. Blokhin Russian Cancer Research Center, Barnaul
| | - V V Klimachev
- Department of Morbid Anatomy, Altai Medical University, Barnaul
| | - A F Lazarev
- Laboratory of Molecular Diagnosis, Altai Branch, N.N. Blokhin Russian Cancer Research Center, Barnaul
| | - E L Lushnikova
- Research Institute of Regional Pathology and Pathomorphology, Siberian Branch, Russian Academy of Medical Sciences, Novosibirsk
| | - L M Nepomnyaschikh
- Research Institute of Regional Pathology and Pathomorphology, Siberian Branch, Russian Academy of Medical Sciences, Novosibirsk
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22
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Kobyakov DS, Avdalyan AM, Bobrov IP, Bychkova EY, Lazarev AF, Lushnikova EL, Nepomnyashchikh LM. Correlation of HER-2/Neu protein expression and HER2 gene amplification with clinical morphological parameters of nonsmall cell lung cancer. Bull Exp Biol Med 2014; 157:789-93. [PMID: 25348568 DOI: 10.1007/s10517-014-2668-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Indexed: 11/24/2022]
Abstract
A total of 218 operation specimens from patients with nonsmall cell lung cancer were examined. The expression of HER-2 protein was studied by the immunohistochemical method, amplification of HER2 gene and centromere part of chromosome 17 (CEP17) - by the in situ chromogenic hybridization method. Moderate correlation (r=0.38, p<0.001) between the immunohistochemical status and HER2 gene amplification was detected. A relationship between TNM clinical morphological parameters and HER-2 protein content and chromosome 17 polysomia (for N parameter), HER-2 protein content, and HER2 gene amplification (for tumor histogenesis) was detected. The content of HER-2 protein and amplification of HER2 and CEP17 correlated with the clinical morphological parameters of patients with nonsmall cell lung cancer.
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Affiliation(s)
- D S Kobyakov
- Altai Affiliated Branch of N. N. Blokhin Russian Cancer Center, Russian Academy of Medical Sciences, Barnaul, Russia,
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Yoshizawa A, Sumiyoshi S, Sonobe M, Kobayashi M, Uehara T, Fujimoto M, Tsuruyama T, Date H, Haga H. HER2 status in lung adenocarcinoma: A comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations. Lung Cancer 2014; 85:373-8. [DOI: 10.1016/j.lungcan.2014.06.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 06/02/2014] [Accepted: 06/08/2014] [Indexed: 11/26/2022]
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Simon GR. nab-Paclitaxel for the treatment of advanced squamous non-small-cell lung cancer: a comprehensive update. Clin Lung Cancer 2014; 15:391-7. [PMID: 25246384 DOI: 10.1016/j.cllc.2014.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 07/21/2014] [Accepted: 07/29/2014] [Indexed: 01/28/2023]
Abstract
Despite advances in the treatment of patients with nonsquamous non-small-cell lung cancer (NSCLC), lung cancer remains a leading cause of death globally. Studies have demonstrated that survival varies according to histological subtype, and, in many cases, patients with squamous NSCLC have a poorer survival rate than those with nonsquamous NSCLC. For patients with squamous NSCLC, platinum-based doublets remain the standard first-line therapy option. This is in part because of the efficacy and safety concerns with some of the approved therapies and is secondary to the observation that many of the mutations targetable with currently approved therapies are rare in patients with squamous NSCLC. Recently, a subset analysis of a completed phase III trial demonstrated that use of nab-paclitaxel with carboplatin led to improved responses in patients with squamous NSCLC compared with solvent-based paclitaxel with carboplatin. In this review, the current experience and evolving role of nab-paclitaxel with carboplatin in the treatment of squamous NSCLC is discussed.
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Affiliation(s)
- George R Simon
- The University of Texas M.D. Anderson Cancer Center, Houston, TX.
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25
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HER2/neu: an increasingly important therapeutic target. Part 2: Distribution of HER2/neu overexpression and gene amplification by organ, tumor site and histology. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.62] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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26
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Shtivelman E, Hensing T, Simon GR, Dennis PA, Otterson GA, Bueno R, Salgia R. Molecular pathways and therapeutic targets in lung cancer. Oncotarget 2014; 5:1392-433. [PMID: 24722523 PMCID: PMC4039220 DOI: 10.18632/oncotarget.1891] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.
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Lung cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Abstract
Cancer of the esophagus is an aggressive disease with early lymphatic and hematogenous dissemination and at present often considered as one clinical entity because of their comparable increasing incidence, prognosis and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Despite recent advances, treatment of upper gastrointestinal malignancies remains a significant challenge. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. This review summarizes the rationale, preclinical evidence, retrospective clinical analyses and the interim clinical data pertaining HER2 therapy and many other molecular pathways.
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Affiliation(s)
- Vinayak Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, NSW, Australia
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Han Y, Li G, Su C, Ren H, Chu X, Zhao Q, Zhu Y, Wang Z, Hu B, An G, Kang J, Wang W, Yu D, Song X, Xiao N, Li Y, Li X, Yang H, Yu G, Liu Z. Exploratory study on the correlation between 14 lung cancer-related gene expression and specific clinical characteristics of NSCLC patients. Mol Clin Oncol 2013; 1:887-893. [PMID: 24649266 PMCID: PMC3915665 DOI: 10.3892/mco.2013.153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 05/15/2013] [Indexed: 12/20/2022] Open
Abstract
Personalized medicine has become essential in the treatment of lung cancer. However, the lung cancer-related gene expression profiles in non-small cell lung cancer (NSCLC) patients have not been elucidated. In this study, the correlation between gene expression profiles and clinicopathological characteristics was investigated in NSCLC patients. A total of 95 patients were enrolled in this study. The mRNA expression levels of 14 genes were assessed by multiplex branched DNA liquidchip (MBL) technology and data on 9 clinicopathological characteristics of patients were collected simultaneously. The correlation between gene expression and clinicopathological characteristics was investigated. Out of the 9 clinicopathological parameters, 6 were associated with several of the 14 genes analyzed. Patient gender was associated with TYMS and TOP2A. Clinical stage was associated with VEGFR2, KIT and HER2. There was weak correlation between primary tumor size of ≤3 cm and the expression level of KIT. The mRNA expression levels of VEGFR2 and HER2 correlated with distant metastasis. BRCA1, TYMS, TOP2A and HER2 were associated with histological type. Smoking correlated with higher expression levels of BRCA1, TYMS and TOP2A and lower expression levels of PDGFRβ. The results were suggestive of correlation between the clinicopathological parameters of the NSCLC patients and the mRNA expression levels of certain lung cancer-related genes, including BRCA1, TYMS, TOP2A, PDGFRβ, VEGFR2, KIT and HER2.
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Affiliation(s)
- Yi Han
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Guo Li
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Chongyu Su
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Hua Ren
- General Hospital of the Chinese Armed Police Forces, Beijing 100039, P.R. China
| | - Xiangyang Chu
- Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Qiuyue Zhao
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Yanjun Zhu
- General Hospital of the Air Force, PLA, Beijing 100142, P.R. China
| | - Zitong Wang
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Bin Hu
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Guangyu An
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Jingbo Kang
- Navy General Hospital, Beijing 100048, P.R. China
| | - Wei Wang
- Navy General Hospital, Beijing 100048, P.R. China
| | - Daping Yu
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Xiaoyun Song
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Ning Xiao
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Yunsong Li
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
| | - Xia Li
- SurExam Bio-Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou 510663, P.R. China
| | - Huiyi Yang
- SurExam Bio-Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou 510663, P.R. China
| | - Gang Yu
- SurExam Bio-Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou 510663, P.R. China
| | - Zhidong Liu
- Department of Thoracic Surgery, Beijing Chest Hospital, Beijing 101149, P.R. China
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Grob TJ, Kannengiesser I, Tsourlakis MC, Atanackovic D, Koenig AM, Vashist YK, Klose H, Marx AH, Koops S, Simon R, Izbicki JR, Bokemeyer C, Sauter G, Wilczak W. Heterogeneity of ERBB2 amplification in adenocarcinoma, squamous cell carcinoma and large cell undifferentiated carcinoma of the lung. Mod Pathol 2012; 25:1566-73. [PMID: 22899293 DOI: 10.1038/modpathol.2012.125] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The HER2 protein, encoded by the ERBB2 gene, is a molecular target for the treatment of breast and gastric cancer by monoclonal antibodies or tyrosine kinase inhibitors. While intratumoral heterogeneity of ERBB2 amplification is rare in breast cancer it is reported to be frequent in bladder and colorectal cancer. To address the potential heterogeneity of the HER2 status in adenocarcinomas, squamous cell carcinomas and large cell undifferentiated carcinomas of the lung, 590 tumors were analyzed for HER2 overexpression and ERBB2 amplification using FDA-approved reagents for immunohistochemistry and fluorescence in-situ hybridization (FISH). Moderate and strong immunostaining (2+, 3+) was seen in 10% of the tumors. ERBB2 amplification was found in 17 (3%) lung cancer patients including 10 cases (2%) with high-level amplification forming gene clusters. ERBB2 amplification was significantly related to histologic subtype and tumor grade, resulting in 12% ERBB2 amplified tumors in the subgroup of high-grade adenocarcinomas. Heterogeneity was analyzed in all highly amplified tumors. For this purpose, all available tumor tissue blocks from these patients were evaluated. Heterogeneity of ERBB2 amplification was found in 4 of 10 tumors as assessed by FISH. These included two tumors with a mixture of low-level and high-level amplification and two tumors with non-amplified tumor areas next to regions with high-level ERBB2 amplification. High-level ERBB2 amplification occurs in a small fraction of lung cancers with a strong propensity to high-grade adenocarcinomas. Heterogeneity of amplification may limit the utility of anti-HER2 therapy in some of these tumors. Further attempts to assess the utility of HER2-targeting therapy in homogeneously amplified lung cancers appear to be justified.
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Affiliation(s)
- Tobias J Grob
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Zeng S, Yang Y, Tan Y, Lu C, Pan Y, Chen L, Lu G. ERBB2-induced inflammation in lung carcinogenesis. Mol Biol Rep 2012; 39:7911-7. [DOI: 10.1007/s11033-012-1635-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 04/16/2012] [Indexed: 10/28/2022]
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Panagiotou I, Georgiannos SN, Tsiambas E, Karameris A, Konstantinou M, Lazaris AC, Kavantzas N, Vilaras G, Patsouris E. Impact of HER2 and PTEN simultaneous deregulation in non-small cell lung carcinoma: correlation with biological behavior. Asian Pac J Cancer Prev 2012; 13:6311-8. [PMID: 23464451 DOI: 10.7314/apjcp.2012.13.12.6311] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND HER2/neu overexpression due to gene amplification is an important factor in breast cancer, modifying the sensitivity to anti-HER2 monoclonal antibody therapy. The clinical significance of HER2 expression in non small cell lung carcinoma (NSCLC) is currently under evaluation. The tumor suppressor gene PTEN negatively regulates the HER2/PI3K/Akt signalling pathway. The purpose of this study was to evaluate the role of simultaneous alteration in HER2 and PTEN protein expression in relation to biological behaviour of NSCLCs. MATERIALS AND METHOD Protein expression was determined by immunohistochemistry in sixty-one (n=61) NSCLC cases along with CISH for HER2 gene analysis and detection of chromosome 17 aneuploidy. Patients were followed-up for a period of 34 to 41 months after surgery. RESULTS HER2 overexpression (2+/3+ score) was detected in 17 (27.9%) patients while loss of PTEN expression was observed in 24 (39.3%) cases, low expression in 29 (47.6%) and overexpression in 8 (13.1%). Simultaneous HER2 overexpression and PTEN low/loss of expression were correlated with metastasis (71.4% vs 36.2% p=0.03) . Analysis in the subgroup of 22 patients of pTNM stage III with lymph node status N1 or N2 revealed that there was a relationship between the number of positive regional lymph node groups and simultaneous deregulation of the two genes (p=0.04). Multivariate analysis determined that HER2 overexpression was associated with an increasing risk of developing metastases (OR: 4.3; 95%CI: 1.2-15.9; p: 0.03) while PTEN overexpression was associated with lower risk (OR: 0.1; 95%CI: 0.1, 1.0; p: 0.05). CONCLUSIONS Simultaneous HER2/PTEN deregulation is a significant genetic event that leads to a more aggressive phenotype of NSCLC.
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Affiliation(s)
- Ioannis Panagiotou
- Department of Thoracic Surgery, 401 General Military Hospital, Athens, Greece.
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Abstract
Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. Understanding the molecular causes of this heterogeneity, which might reflect changes occurring in different classes of epithelial cells or different molecular changes occurring in the same target lung epithelial cells, is the focus of current research. Identifying the genes and pathways involved, determining how they relate to the biological behavior of lung cancer, and their utility as diagnostic and therapeutic targets are important basic and translational research issues. This article reviews current information on the key molecular steps in lung cancer pathogenesis, their timing, and clinical implications.
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Affiliation(s)
- Jill E Larsen
- Hamon Center for Therapeutic Oncology Research, Simmons Cancer Center, 6000 Harry Hines Boulevard, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA
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Yan YY, Zheng LS, Zhang X, Chen LK, Singh S, Wang F, Zhang JY, Liang YJ, Dai CL, Gu LQ, Zeng MS, Talele TT, Chen ZS, Fu LW. Blockade of Her2/neu binding to Hsp90 by emodin azide methyl anthraquinone derivative induces proteasomal degradation of Her2/neu. Mol Pharm 2011; 8:1687-97. [PMID: 21812426 DOI: 10.1021/mp2000499] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Overexpression of HER2/neu, a transmembrane tyrosine kinase acting as a coreceptor for other EGFR family members, is well-known to be associated with a poor prognosis in cancer. In the present study, we observed that emodin AMAD, a novel emodin azide methyl anthraquinone derivative, extracted from nature's giant knotweed rhizome of traditional Chinese herbs, potently decreased Her2/neu protein in dose- and time-dependent manners and also inhibited the downstream MAPK and PI3K-Akt signaling pathway. Intriguingly, reverse transcription-PCR and protein turnover assay revealed that the decrease of Her2/neu was independent of mRNA level but primarily owing to its protein stability. Meanwhile, proteasome inhibitor MG132 but not lysosome inhibitor chloroquine could restore Her2/neu and polyubiquitination of Her2/neu was augmented during emodin AMAD treatment. Furthermore, immunofluorescence study with anti-Her2/neu antibody showed that emodin AMAD disturbed the subcellular distribution of Her2/neu, with decreased location in the plasma membrane. Molecular docking studies predicted that AMAD can interact with the ATP-binding pocket of both Hsp90 and Her2/neu. Importantly, coimmunoprecipitation and immunofluorescence study revealed that emodin AMAD markedly impaired the binding between Hsp90 and Her2/neu and could bind to both Hsp90 and Her2/neu as reinforced by molecular modeling studies. In addition, combination of emodin AMAD treatment and siRNA against Her2 synergistically inhibited proliferation and induced apoptosis. Taken together, these data suggest that blockade of Her2/neu binding to Hsp90 and following proteasomal degradation of Her2/neu were involved in emodin AMAD-induced apoptosis in Her2/neu-overexpressing cancer cells. Our results provide suggestions that emodin AMAD could be promising as a new targeting therapeutic strategy in the treatment of Her2/neu-overexpressing cancers.
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Affiliation(s)
- Yan-yan Yan
- State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, People's Republic of China
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Al-Qahtani A, Al-Hazzani T, Al-hussain T, Al-Ghamdi A, Al-Mana H, Al-Arifi S, Al-Ahdal M, Aly M. Correlation between clinical characteristics, survival and genetic alterations in patients with hepatocellular carcinoma from Saudi Arabia. ACTA ACUST UNITED AC 2010; 203:269-77. [PMID: 21156243 DOI: 10.1016/j.cancergencyto.2010.08.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2010] [Revised: 07/30/2010] [Accepted: 08/08/2010] [Indexed: 11/25/2022]
Abstract
Amplification of the two oncogenes ERBB2 and MYC and deletion of the tumor suppressor gene TP53 are frequently encountered in cancerous tissues. The purpose of this study was to use the fluorescence in situ hybridization (FISH) technique for the assessment of ERBB2 and MYC amplification and TP53 deletion, and to relate these molecular markers to clinical and pathologic factors in Saudi patients with hepatocellular carcinoma. The study was conducted on 40 paraffin-embedded tissue samples originally taken from either hepatitis C virus (HCV)- or HBV-infected patients using the FISH technique. The level of ERBB2, MYC, and TP53 in the malignant group was significantly increased as compared to the control group. Of the 40 patients, 3 (7.5%) had amplification of ERBB2 gene, 4 (10%) different patients had amplification of MYC, and 26 patients (65%) had evidence of deletion of at least one allele on chromosome 17 for the TP53 gene in a high proportion of cells. There was a significant correlation between amplification of MYC oncogene and the number of tumor masses. Moreover, significant correlation was observed between poorly differentiated tumors when compared with moderate or well-differentiated tumors when MYC was analyzed. On the other hand, MYC failed to reveal any significant association between oncogene amplification and other clinicopathologic variables examined. Univariate analysis revealed a strong association between deletion of TP53 and multiple tumor mass (P< 0.001). No statistical correlation could be detected between deletion of TP53 and tumor size, grade, stage, and tumor differentiation. No significant difference could be detected in the mean survival time of patients positive for the alteration of the genes compared to the patients who showed no alterations for the same genes. However, when the stage of the tumor was analyzed, there was a significant difference in the mean survival time between patients who showed gene alterations compared to patients with no changes in the studied genes. When overall survival was analyzed, only patients with MYC amplification had a lower median survival (20.75 months) than patients without MYC amplification (35.82, P = 0.009). Genetic alterations of ERBB2 and TP53 genes had no effect on survival 2 (see Results). The combination of ERBB2, MYC, and TP53 could be useful markers to stratify patients into different risk groups.
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Affiliation(s)
- Ahmed Al-Qahtani
- Biological and Medical Research MBC 03, King Faisal Specialist Hospital and Research Centre, Box 3344 MBC-03, Riyadh 11211, Saudi Arabia
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The Role of Human Epidermal Growth Factor Receptor 2 as a Prognostic Factor in Lung Cancer: A Meta-Analysis of Published Data. J Thorac Oncol 2010; 5:1922-32. [PMID: 21155183 DOI: 10.1097/jto.0b013e3181f26266] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Tsai WC, Lee MY, Chen FL, Wang PH, Lin WL, Ruan A, Li YJ, Wang SC, Chiang H, Han CP. The HER2 gene copies per tumor cell either before or after correction for chromosome-17 correlated significantly with HER2 IHC results in epithelial ovarian cancer in a tissue microarray study. Arch Gynecol Obstet 2010; 284:721-9. [PMID: 21046136 DOI: 10.1007/s00404-010-1708-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 08/24/2010] [Indexed: 11/26/2022]
Abstract
BACKGROUND HER2 gene amplification and HER2 protein overexpression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast cancer patients. The purpose of this study is to evaluate the correlation between HER2 protein expressions and the HER2 gene copies per tumor cell either before or after chromosome-17 correction in epithelial ovarian cancer (EOC). METHODS Adopting 2007 ASCO/CAP guideline recommendations for HER2 testing, 27 tissue microarray (TMA) samples from EOC patients were analyzed by immunohistochemistry (IHC) using Dako, c-erb-B2 antibody and subsequently examined by fluorescence in situ hybridization (FISH) using Abbott/Vysis, PathVysion HER2 DNA Probe Kit. RESULTS The overall concordance revealed 81.5% between HER2 IHC and HER2 FISH results. Additionally, HER2 gene copies prior to chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal, and positive IHC result categories (P = 0.026), as did the HER2 gene copies after chromosome-17 correction (P = 0.028). On the other hand, HER2 IHC results correlated significantly with both chromosome-17 uncorrected HER2 gene copy numbers (ρ = 0.430, P = 0.025) and chromosome-17 corrected HER2 gene copy numbers (ρ = 0.524, P = 0.027). CONCLUSION We demonstrated that both chromosome-17 corrected and uncorrected HER2 gene copies correlated significantly with HER2 IHC result categories; and tests for the HER2 gene copies per tumor cell either before or after correction for chromosome-17 can be applied as a potentially valuable tool in analyzing the HER2 status in EOC.
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Affiliation(s)
- Wen-Chih Tsai
- Department of Obstetrics and Gynecology, Po-Jen General Hospital, Taipei, Taiwan
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Inhibition of ErbB2 by herceptin reduces viability and survival, induces apoptosis and oxidative stress in Calu-3 cell line. Mol Cell Biochem 2010; 347:41-51. [PMID: 20936496 DOI: 10.1007/s11010-010-0610-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2010] [Accepted: 09/28/2010] [Indexed: 12/28/2022]
Abstract
Human epidermal growth factor receptor 2 (ErbB2) amplification and overexpression has been seen in many cancer types including non-small cell lung cancer (NSCLC). Thus, ErbB2 is an important target for cancer therapies. Increased ErbB2 expression has been associated with drug resistance in cancer cells. Herceptin is a humanized monoclonal antibody that targets the extracellular domain of ErbB2. In this study, we aimed to block ErbB2 signaling with Herceptin and assess cytotoxicity and effects on apoptosis, oxidative stress, nuclear factor kappa-B (NF-kB), and Survivin expression in Calu-3 cell line. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay were used to assess cell viability as a marker of proliferation. Acridine orange/ethidium bromide (AO/EB) staining and caspase 3/7 activity were measured as the markers of apoptosis. The relative expressions of NF-kB-p50 and Survivin mRNAs were evaluated. Activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), and the levels of glutathione (GSH) and reactive oxygen species (ROS) were determined in a time- and dose-dependent manner. Our results show that Herceptin treatment inhibits cell proliferation and activates apoptosis but without effects on Survivin and NF-kB expression in Calu-3 cell line. Intracellular glutathione levels and SOD and CAT activities were decreased in a time- and dose-dependent manner associated with oxidative stress. Also, ROS were increased at 24 h. These results provide evidence that Herceptin can be used as a cytotoxic and apoptotic agent in NSCLC.
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Impact of HER2 gene and protein status on the treatment outcome of cisplatin-based chemoradiotherapy for locally advanced non-small cell lung cancer. J Thorac Oncol 2008; 3:477-82. [PMID: 18448999 DOI: 10.1097/jto.0b013e31816e2ea3] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND It has not been fully evaluated whether both HER2 gene copy number and HER2 protein expression are related to the outcome of chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The aim of this study was to evaluate their relationships. METHODS HER2 gene copy number determined by fluorescence in situ hybridization (FISH) and HER2 protein expression determined by immunohistochemistry (IHC) were assessed in 68 patients with LA-NSCLC enrolled in our previous phase II trials of concurrent cisplatin-based chemoradiotherapy, and a multivariate analysis was conducted for response and survival. RESULTS HER2-IHC-positive tumors were detected in 23 patients (34%), and the median ratio of HER2 to chromosome 17 copy number was 0.93 (range, 0.55-2.00). The HER2-FISH results were marginally correlated with the IHC results (p = 0.0715). When the median ratio in the FISH analysis was used as a cut-off level for its positivity, there was no association between either HER2-FISH or IHC status and objective response to chemoradiotherapy. Contrary, a multivariate analysis revealed HER2-FISH result but not IHC result was an independent poor prognostic factor for both overall survival and progression-free survival (hazard ratio = 2.568, 95% confidence interval [CI] = 1.117-5.903, p = 0.0264 and hazard ratio = 2.283, 95% CI = 1.005-5.189, p = 0.0487, respectively). CONCLUSIONS Patients with HER2 FISH-positive LA-NSCLC had a poorer outcome even when treated with cisplatin-based chemoradiotherapy, despite the strong need for validation assessment of these observations. Development of more effective treatment for these high-risk patients is needed to improve their poor prognosis.
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Soh J, Toyooka S, Ichihara S, Fujiwara Y, Hotta K, Suehisa H, Kobayashi N, Ichimura K, Aoe K, Aoe M, Kiura K, Date H. Impact of HER2 and EGFR gene status on gefitinib-treated patients with nonsmall-cell lung cancer. Int J Cancer 2007; 121:1162-7. [PMID: 17487844 DOI: 10.1002/ijc.22818] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We previously examined the relationship between epidermal growth factor receptor (EGFR) status and clinical outcomes of nonsmall-cell lung cancer (NSCLC) patients treated with gefitinib. In our study, we additionally examined HER2 status and investigate the impact of genetic status as predictors in Japanese NSCLC patients treated with gefitinib. The HER2 copy number status was determined by fluorescence in situ hybridization assay and mutation of HER2 exon 20 was determined by direct sequencing in 74 patients to investigate the relationship between molecular statuses including HER2 and EGFR and the clinical outcomes of patients treated with gefitinib. The high HER2 copy number was identified in 32 (43.2%) of 74 NSCLC patients and no HER2 exon 20 mutations were found. The high HER2 copy number was significantly associated with the sensitivity to gefitinib (p = 0.0045) and a prolonged progression-free survival (PFS) (p = 0.0089) in a univariate analysis, but not in a multivariate analysis. Multivariate analyses exhibited that the drug-sensitive EGFR mutation was an independent predictive factor of a better sensitivity to gefitinib (OR = 41.9, p = 0.002), prolonged overall survival (HR = 0.32, p = 0.019) and PFS (HR = 0.31, p = 0.0045). The high EGFR copy number might have a weak association with better response and prognosis without statistical significance. In conclusion, the drug-sensitive EGFR mutation, rather than HER2 and EGFR copy numbers, is a determinant of favorable clinical outcomes in gefitinib-treated patients with NSCLC, although the high HER2 copy number, to some extent, may influence the gefitinib effect.
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Affiliation(s)
- Junichi Soh
- Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Reichelt U, Duesedau P, Tsourlakis MC, Quaas A, Link BC, Schurr PG, Kaifi JT, Gros SJ, Yekebas EF, Marx A, Simon R, Izbicki JR, Sauter G. Frequent homogeneous HER-2 amplification in primary and metastatic adenocarcinoma of the esophagus. Mod Pathol 2007; 20:120-9. [PMID: 17143264 DOI: 10.1038/modpathol.3800712] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
HER-2 is the target for antibody based treatment of breast cancer (Herceptin). In order to evaluate the potential role of such a treatment in esophageal cancers, HER-2 amplification and overexpression was investigated in primary and metastatic cancers of the esophagus. A tissue microarray was constructed from 255 primary esophageal cancers (110 adenocarcinomas and 145 squamous cell carcinomas), 89 nodal and 33 distant metastases. Slides were analyzed by immunohistochemistry (HercepTest; DAKO) and fluorescence in situ hybridization (FISH; PathVysion; Vysis-Abbott) for HER-2 amplification and overexpression. Amplification was seen in 16/110 (15%) adenocarcinomas and in 7/145 (5%) squamous cell carcinomas. There was a strong association between HER-2 amplification and overexpression, especially in adenocarcinomas (P<0.0001, log rank). There was a 100% concordance of the HER-2 results in primary tumor and corresponding metastases in 84 analyzed pairs. Amplification was typically high-level with more than 10-15 HER-2 copies per tumor cell. Amplification was unrelated to survival, grading, pT, pN, pM or UICC stage. We conclude that esophageal adenocarcinomas belong to those cancer types with relevant frequency high-level HER-2 gene amplification clinical trials or individual case studies investigating the response of metastatic HER-2-positive esophageal cancers to Herceptin((R)) should be undertaken. The strong concordance of the HER-2 status in primary and metastatic cancers argues for a possible response of metastases from patients with HER-2-positive primary tumors to Herceptin.
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Affiliation(s)
- Uta Reichelt
- Department of Pathology, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany
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Awaya H, Takeshima Y, Furonaka O, Kohno N, Inai K. Gene amplification and protein expression of EGFR and HER2 by chromogenic in situ hybridisation and immunohistochemistry in atypical adenomatous hyperplasia and adenocarcinoma of the lung. J Clin Pathol 2005; 58:1076-80. [PMID: 16189154 PMCID: PMC1770741 DOI: 10.1136/jcp.2004.025585] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIMS To investigate the importance of gene amplification and EGFR (epidermal growth factor receptor) and HER2 protein expression during the progression of adenocarcinoma of the lung. METHODS EGFR and HER2 gene amplification was examined in atypical adenomatous hyperplasia (AAH), bronchioloalveolar carcinoma (BAC), and adenocarcinoma with mixed subtypes (MX) by chromogenic in situ hybridisation (CISH), and protein expression was examined by immunohistochemistry using paraffin wax embedded tissues. RESULTS EGFR and HER2 gene amplification was found in four and two of 86 cases, respectively, and was detected only in the invasive components of MX. EGFR and HER2 protein expression was seen in 24 and 18 of 86 cases, respectively. EGFR and HER2 proteins were not expressed in AAH but were expressed in one BAC case each. EGFR and HER2 proteins were expressed in 23 and 17 of 55 adenocarcinomas with MX. EGFR and HER2 protein expression was seen more often in the invasive components than in the BAC components of MX, and increased significantly as lesions progressed from AAH to BAC, early MX, and overt MX. Because EGFR and HER2 protein expression was frequently seen without gene amplification, other mechanisms apart from gene amplification may be associated with protein expression. CONCLUSIONS EGFR and HER2 gene amplification may be a late event and EGFR and HER2 protein expression may be associated with the development of adenocarcinoma of the lung.
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Affiliation(s)
- H Awaya
- Department of Pathology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Meert AP, Martin B, Verdebout JM, Noël S, Ninane V, Sculier JP. Is there a relationship between c-erbB-1 and c-erbB-2 amplification and protein overexpression in NSCLC? Lung Cancer 2005; 47:325-36. [PMID: 15713516 DOI: 10.1016/j.lungcan.2004.07.047] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2004] [Revised: 07/05/2004] [Accepted: 07/14/2004] [Indexed: 11/17/2022]
Abstract
In order to analyse the genetic abnormalities and protein expression of c-erbB-1 and -2, we have performed fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in resected non-small cell lung carcinoma (NSCLC). By IHC (106 patients), 11% of the patients were positive both for c-erbB-1 and -2 protein expression and 47% negative for both proteins. FISH (69 patients) showed a balanced disomy for both c-erbB-1 and -2 in 38%, all other cases had genetic abnormalities in at least one of both genes. c-erbB-2 gene was amplified in less than 10% of the tumours and c-erbB-1 gene was never amplified. c-erbB-2 protein overexpression was observed in only three out of the six cases showing c-erbB-2 amplification. The negative predictive value (NPV) of IHC for gene abnormalities was high for both markers. Median survival time (MST) was respectively of 76 and 174 weeks for patients with or without c-erbB-2 overexpression. Patients with c-erbB-2 amplification had a shorter survival: 125 weeks versus 165 weeks. MST was respectively of 109 and 196 weeks for patients with or without EGFR overexpression and patients with EGFR gene abnormalities had also a shorter survival with MST 136 weeks versus 189 weeks. These differences were not significant. In conclusion, if the majority of NSCLC showed genetic abnormalities in the c-erbB-1 and/or c-erbB-2 gene receptor, amplification could be observed only in a few tumours and was not strictly correlated with protein expression. Finally, survival of patients expressing EGFR and/or c-erbB-2 was slightly shorter.
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Affiliation(s)
- Anne-Pascale Meert
- Service des Soins Intensifs et Cancérologie Pulmonaire et Laboratoire d'Investigation Clinique et d'Oncologie Expérimentale HJ Tagnon, Institut Jules Bordet, 1 rue Héger Bordet, Bruxelles, Belgique.
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Hirata A, Hosoi F, Miyagawa M, Ueda SI, Naito S, Fujii T, Kuwano M, Ono M. HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res 2005; 65:4253-60. [PMID: 15899817 DOI: 10.1158/0008-5472.can-04-2748] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Gefitinib (Iressa), an epidermal growth factor receptor targeting drug, has been clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). Gefitinib is currently being applied in clinical studies as either a monotherapy, or as part of a combination therapy against prostate, head and neck, gastric, breast, and colorectal tumors. However, success rates vary between different tumor types, and thus it is important to understand which molecular target(s) are responsible for limiting the therapeutic efficacy of the drug. In this study, we ask whether expression of HER2 affects sensitivity to gefitinib in human lung cancer cells. We established two clones, LK2/HER2-32 and LK2/HER2-57, by transfecting HER2 cDNA into LK2, a NSCLC line with a low expression level of HER2. We observed no mutations in exons 18, 19, and 21 of EGFR gene in LK2, LK2/mock- and two HER2-trasfectants when we observed in-frame deletion mutations (E746-A750) adjacent to K745 in a gefitinib-sensitive NSCLC cell line, PC9. These LK2/HER2-32 and LK2/HER2-57 were much more sensitive to the cytotoxic effects of gefitinib than the parental LK2 lines. Treatment with 0.5 to 1 micromol/L gefitinib specifically blocked Akt activation in both HER2-transfectant lines, but not in the parental LK2 cells. Extracellular signal-regulated kinase-1/2 activation, however, was not blocked by gefitinib up to 10 micromol/L in either the parent or transfectant lines. Gefitinib was also shown to induce cell cycle arrest in the G1-S phase, and an accompanying increase of p27Kip1 was observed. LK2/HER2 transfectants showed constitutive formation of HER2/HER3 heterodimer, which were seen to associate with a regulatory subunit of phosphoinositide-3-kinase, p85alpha, when active. Treatment of LK2/HER2 cells with gefitinib markedly decreased the formation of HER2/HER3 heterodimers, HER3 basal phosphorylation, and the association of p85alpha with HER3. This study is the first to show that under basal growth conditions, HER2 sensitizes low-EGFR NSCLC cell lines to growth inhibition by gefitinib.
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Affiliation(s)
- Akira Hirata
- Departments of Medical Biochemistry and Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka.
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Nakamura H, Kawasaki N, Taguchi M, Kabasawa K. Association of HER-2 overexpression with prognosis in nonsmall cell lung carcinoma: a metaanalysis. Cancer 2005; 103:1865-73. [PMID: 15770690 DOI: 10.1002/cncr.20957] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Prognostic implications of overexpression of the HER-2 gene in nonsmall cell lung carcinoma (NSCLC) are a matter of controversy. Many conflicting results have been reported from different laboratories. METHODS A metaanalysis of published studies was performed for this quantitative review of the effects of HER-2 overexpression on survival among patients with NSCLC. Of 44 articles initially selected, 20 articles fulfilled eligibility criteria. DerSimonian-Laird random effects analysis was used to estimate the effects of HER-2 overexpression on survival differences (the survival rate among patients without HER-2 overexpression minus the survival rate among patients with HER-2 overexpression) at endpoints of 1 years, 3 years, and 5 years after resection of NSCLC. RESULTS In total, 2579 patients were included in the final analysis. Overall, HER-2 positivity differed according to histologic type and included 38% of patients with adenocarcinoma, 16% of patients with squamous cell carcinoma, and 18% of patients with large cell carcinoma (P < 0.0001). The combined survival differences in patients with NSCLC at 1 year, 3 years, and 5 years, respectively, were 2.7% (95% confidence interval [95% CI], 1.3-6.7%; P = 0.1787), 15.2% (95% CI, 5.8-24.5%; P = 0.0015), and 16.4% (95% CI, 7.9-14.8%; P = 0.0001), suggesting significant poorer survival at 3 years and 5 years among patients with HER-2 overexpression. In patients with adenocarcinoma, the combined survival difference at 5 years was 26.0% (95% CI, 16.0-36.1%; P < 0.0001), suggesting a particularly strong survival impact for HER-2 overexpression. CONCLUSIONS A significant, unfavorable prognostic effect of HER-2 overexpression in NSCLC was evident from the metaanalysis. However, because several studies that found no significant difference were excluded by the current eligibility criteria, caution is needed in interpreting the results.
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Affiliation(s)
- Haruhiko Nakamura
- Department of Chest Surgery, Atami Hospital, International University of Health and Welfare, Shizuoka, Japan.
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46
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Massoner A, Augustin F, Duba HC, Zojer N, Fiegl M. FISH cytogenetics and prognosis in breast and non-small cell lung cancers. CYTOMETRY PART B-CLINICAL CYTOMETRY 2005; 62:52-6. [PMID: 15468329 DOI: 10.1002/cyto.b.20023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Interphase cytogenetics by fluorescence in situ hybridization (FISH) has been demonstrated to be a valuable diagnostic tool in effusions from patients with solid tumors. As the next step, we investigated whether certain patterns of numeric aberrations in malignant effusion cells supply prognostic information. METHODS From a large series of effusions from patients with solid tumors, 55 effusions from breast cancer and 39 effusions from non-small cell lung cancer (NSCLC) were classified as malignant by cytology or FISH. Tumor cells were classified as FISH aneuploid for chromosome 11 and/or 17 or as not aneuploid. Predominant cytogenetic anomalies and patterns of intratumor cytogenetic heterogeneity were brought in relation to overall survival rate. RESULTS There was no difference with respect to overall survival rate when effusions with or without aneuploidy for chromosomes 11 and 17 were compared. Likewise, in effusions with aneuploidy, there was no difference in overall survival rate among patients with different modal chromosome copy numbers (e.g., trisomy vs. tetrasomy 11) or among patients with a low or high grade of intratumor complexity (defined by the intratumor heterogeneity of FISH aneuploidy). In breast cancer, aneuploidy with gain of chromosome 11 was associated with a significantly superior survival rate, suggesting that amplification of chromosome 11 DNA is associated with a less aggressive phenotype. CONCLUSIONS Simple chromosomal changes as determined by FISH, such as gain of chromosome 11 copy numbers in breast cancer, may be prognostic. Prospective studies in primary tumors that classify distinct prognostic groups by FISH cytogenetics are warranted.
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Affiliation(s)
- Anita Massoner
- Department of Internal Medicine, Division of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
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Fischer JR, Lahm H. Validation of molecular and immunological factors with predictive importance in lung cancer. Lung Cancer 2004; 45 Suppl 2:S151-61. [PMID: 15552796 DOI: 10.1016/j.lungcan.2004.07.978] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Histological classification and staging are cornerstones of diagnosis in lung cancer. Treatment options have been enriched in the last few years by the development of a number of new drugs, and therapy is now increasingly being carried out within multimodal concepts and at earlier stages. Still, outcome of the disease is far from satisfactory and progress in clinical and preclinical research is time-consuming. With the whole variety of potent new therapeutic compounds including classical cytostatics and biological factors at hand, many now believe that a clear improvement of treatment results will be derived from a better understanding of the biology of these tumours and a resulting improvement of diagnosis. Biological factors reflecting the underlying tumour biology and aspects of clinically important pathomechanisms may not only better predict outcome of the disease but also of its treatment, serving as surrogate markers for a more appropriate general intensification of therapy and ideally for specific "targeted" interventions. This article describes the different insights in the biology of these tumours in relation with the representing surrogate markers, and opens routes to possible diagnostic and therapeutic consequences.
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Affiliation(s)
- Jürgen R Fischer
- Klinik für Innere Medizin II Onkologie, Zentrum für Thoraxerkrankungen Löwenstein gGmbH, D-74245 Lowenstein, Germany.
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Van Den Bossche B, Van de Wiele C. Receptor Imaging in Oncology by Means of Nuclear Medicine: Current Status. J Clin Oncol 2004; 22:3593-607. [PMID: 15337810 DOI: 10.1200/jco.2004.10.216] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
To date, our understanding of the role of receptors and their cognate ligands in cancer is being successfully translated into the design and development of an arsenal of new, less toxic, and more specific anticancer drugs. Because most of these novel drugs are cytostatic, objective response as measured by morphologic imaging modalities (eg, computed tomography or magnetic resonance imaging) cannot be used as a surrogate marker for drug development or for clinical decision making. Positron emission tomography (PET) can be used to image and quantify the in vivo distribution of positron-emitting radioisotopes such as oxygen-15, carbon-11, and fluorine-18 that can be substituted or added into biologically relevant and specific receptor radioligands. Similarly, single-photon emission computed tomography (SPECT) can be used to image and quantify the in vivo distribution of receptor targeting compounds labeled with indium-111, technetium-99m, and iodine-123. By virtue of their whole-body imaging capacity and the absence of errors of sampling and tissue manipulation as well as preparation, both techniques have the potential to address locoregional receptor status noninvasively and repetitively. This article reviews available data on the in vivo evaluation of receptor systems by means of PET or SPECT for identifying and monitoring patients with sufficient receptor overexpression for tailored therapeutic interventions, and also for depicting tumor tissue and determining the currently largely unknown heterogeneity in receptor expression among different tumor lesions within and between patients.
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Lara PN, Laptalo L, Longmate J, Lau DHM, Gandour-Edwards R, Gumerlock PH, Doroshow JH, Gandara DR. Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial. Clin Lung Cancer 2004; 5:231-6. [PMID: 14967075 DOI: 10.3816/clc.2004.n.004] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.
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MESH Headings
- Adenocarcinoma/drug therapy
- Adenocarcinoma/metabolism
- Adenocarcinoma, Bronchiolo-Alveolar/drug therapy
- Adenocarcinoma, Bronchiolo-Alveolar/metabolism
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal, Humanized
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- California
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/metabolism
- Docetaxel
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Female
- Humans
- Immunohistochemistry
- Lung Neoplasms/drug therapy
- Lung Neoplasms/metabolism
- Male
- Mass Screening
- Middle Aged
- Receptor, ErbB-2/biosynthesis
- Taxoids/administration & dosage
- Trastuzumab
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Affiliation(s)
- Primo N Lara
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Cancer Center, Sacramento, CA 95817, USA.
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50
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Rosell R. Toward Customized Trastuzumab in HER-2/neu-Overexpressing Non-Small-Cell Lung Cancers. J Clin Oncol 2004; 22:1171-3. [PMID: 14981109 DOI: 10.1200/jco.2004.01.904] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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