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Wang J, Dong X, Liu Y, Lin K, Chen J. Copy number gain of MET gene with low level in a metastatic lung adenocarcinoma patient represents response to salvage treatment with savolitinib and osimertinib: a case report. Front Oncol 2025; 15:1507677. [PMID: 40365349 PMCID: PMC12069039 DOI: 10.3389/fonc.2025.1507677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
Background Mesenchymal-epithelial transition (MET) amplification is one of the molecular mechanisms of abnormal MET oncogenic signaling in non-small cell lung cancer (NSCLC), significantly contributing to tumor cell survival, proliferation, metastasis, and drug resistance. The results of the TATTON trial showed that the combination of savolitinib and osimertinib can prolong the survival of patients with advanced EGFR-TKI-resistant NSCLC and high-level acquired MET amplification. Case presentation We present a case of an NSCLC patient who exhibited acquired MET amplification with a gene copy number (GCN) of 3 following resistance to EGFR-TKI. The patient achieved a substantial response to salvage therapy with savolitinib and osimertinib, resulting in a 7-month progression-free survival (PFS). Conclusions We considered that a regimen of savolitinib + osimertinib combination sometimes may still be potentially beneficial for NSCLC patients with low-GCN-level MET amplification. However, it needs further confirmation in a larger cohort.
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Affiliation(s)
- Jian Wang
- M.D. Department of Medical Oncology, International Ward, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, China
- M.D. The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xinying Dong
- Changsha Medical University, Changsha, Hunan, China
| | - Yangxin Liu
- Changsha Medical University, Changsha, Hunan, China
| | - Keying Lin
- M.D. The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jianxin Chen
- M.D. Department of Medical Oncology, International Ward, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, China
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Bogdanska W, Paik PK. From knowledge to action: The journey toward targeting the MET pathway via MET exon 14 skipping. Cancer 2025; 131 Suppl 1:e35782. [PMID: 40172182 DOI: 10.1002/cncr.35782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/21/2024] [Accepted: 11/15/2024] [Indexed: 04/04/2025]
Abstract
Targeted therapies have radically altered the prognosis of patients with non-small cell lung cancer (NSCLC). Although the MET pathway was characterized in 1984, the treatment paradigm for patients with MET alterations has only recently changed. Genomic alterations in MET are found in 3%-5% of patients with NSCLC, and can include MET exon 14 (METex14) skipping, MET-activating mutations, and MET amplification. These alterations lead to the prolonged activation of the cellular MET receptor and downstream proliferation pathways that drive cell survival and migration. This review explores the history and pathophysiology of the MET pathway by focusing on METex14 skipping, and highlights insights gained since its discovery. Both unsuccessful and successful treatments that have emerged alongside the evolution of next-generation sequencing are examined, as well as current approved therapies and future options that target potential resistance mechanisms.
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Affiliation(s)
- Wiktoria Bogdanska
- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Paul K Paik
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical College, New York, New York, USA
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Peng L, Deng S, Li J, Zhang Y, Zhang L. Single-Cell RNA Sequencing in Unraveling Acquired Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: New Perspectives. Int J Mol Sci 2025; 26:1483. [PMID: 40003951 PMCID: PMC11855476 DOI: 10.3390/ijms26041483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/07/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated remarkable efficacy in treating non-small cell lung cancer (NSCLC), but acquired resistance greatly reduces efficacy and poses a significant challenge to patients. While numerous studies have investigated the mechanisms underlying EGFR-TKI resistance, its complexity and diversity make the existing understanding still incomplete. Traditional approaches frequently struggle to adequately reveal the process of drug resistance development through mean value analysis at the overall cellular level. In recent years, the rapid development of single-cell RNA sequencing technology has introduced a transformative method for analyzing gene expression changes within tumor cells at a single-cell resolution. It not only deepens our understanding of the tumor microenvironment and cellular heterogeneity associated with EGFR-TKI resistance but also identifies potential biomarkers of resistance. In this review, we highlight the critical role of single-cell RNA sequencing in lung cancer research, with a particular focus on its application to exploring the mechanisms of EGFR-TKI-acquired resistance in NSCLC. We emphasize its potential for elucidating the complexity of drug resistance mechanism and its promise in informing more precise and personalized treatment strategies. Ultimately, this approach aims to advance NSCLC treatment toward a new era of precision medicine.
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Affiliation(s)
| | | | | | | | - Li Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (L.P.); (S.D.); (J.L.); (Y.Z.)
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Toumi E, Hesson LB, Lin V, Wright D, Hajdu E, Lim LAS, Giblin M, Zhou F, Hoffmeister A, Zabih F, Fung AT, Conway RM, Cherepanoff S. Microdissection of Distinct Morphological Regions Within Uveal Melanomas Identifies Novel Drug Targets. Cancers (Basel) 2024; 16:4152. [PMID: 39766052 PMCID: PMC11674814 DOI: 10.3390/cancers16244152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/18/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: Uveal melanomas (UMs) are rare but often deadly malignancies that urgently require viable treatment options. UMs often exhibit tumour heterogeneity, with macroscopic and microscopic differences in morphology between different regions of the same tumour. However, to date, the clinical significance of this and how it may help guide personalised therapy have not been realised. Methods: Using targeted DNA and RNA sequencing of a small case series of large, high-risk primary UMs, we explored whether morphologically distinct regions of the same tumour were associated with distinct molecular profiles. Results: In four of the seven tumours analysed, we detected different sets of genetic variants following the separate analysis of microdissected melanotic and amelanotic regions of the same tumour. These included a MET exon 14 skipping RNA transcript that predicts sensitivity to crizotinib and variants in other genes that are important in active clinical trials for patients with UM and advanced solid tumours. The integration of TCGA data also identified recurrent mutational events in genes that were not previously implicated in UM development (FANCA, SLX4, BRCA2, and ATRX). Conclusions: Our findings show that the molecular analysis of spatially separated and morphologically distinct regions of the same tumour may yield additional, therapeutically relevant genetic variants in uveal melanomas and have implications for the future molecular testing of UMs to identify targeted therapies.
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Affiliation(s)
- Elsa Toumi
- Department of Ophthalmology, University Hospital of Nice, 06000 Nice, France;
- SydPath, St Vincent’s Hospital Sydney, Darlinghurst, NSW 2010, Australia; (A.H.)
- Medicine & Health, UNSW Sydney, Randwick, NSW 2031, Australia; (L.B.H.); (V.L.)
| | - Luke B. Hesson
- Medicine & Health, UNSW Sydney, Randwick, NSW 2031, Australia; (L.B.H.); (V.L.)
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
- Department of Molecular Genetics, Douglass Hanly Moir Pathology, Macquarie Park, NSW 2113, Australia
| | - Vivian Lin
- Medicine & Health, UNSW Sydney, Randwick, NSW 2031, Australia; (L.B.H.); (V.L.)
| | - Dale Wright
- Department of Cytogenetics, Sydney Genome Diagnostics, The Children’s Hospital at Westmead, Westmead, NSW 2145, Australia;
- Discipline of Paediatrics & Child Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Elektra Hajdu
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
| | - Li-Anne S. Lim
- Ocular Oncology Unit, Sydney Eye Hospital, Sydney, NSW 2000, Australia; (L.-A.S.L.); (M.G.); (R.M.C.)
| | - Michael Giblin
- Ocular Oncology Unit, Sydney Eye Hospital, Sydney, NSW 2000, Australia; (L.-A.S.L.); (M.G.); (R.M.C.)
| | - Fanfan Zhou
- Sydney Pharmacy School, The University of Sydney, Sydney, NSW 2050, Australia;
| | | | - Farida Zabih
- SydPath, St Vincent’s Hospital Sydney, Darlinghurst, NSW 2010, Australia; (A.H.)
| | - Adrian T. Fung
- Westmead and Central Clinical Schools, Specialty of Ophthalmology and Eye Health, The University of Sydney, Sydney, NSW 2050, Australia;
- Department of Ophthalmology, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2113, Australia
| | - R. Max Conway
- Ocular Oncology Unit, Sydney Eye Hospital, Sydney, NSW 2000, Australia; (L.-A.S.L.); (M.G.); (R.M.C.)
| | - Svetlana Cherepanoff
- SydPath, St Vincent’s Hospital Sydney, Darlinghurst, NSW 2010, Australia; (A.H.)
- Medicine & Health, UNSW Sydney, Randwick, NSW 2031, Australia; (L.B.H.); (V.L.)
- School of Medicine, University of Notre Dame, Sydney Campus, Darlinghurst, NSW 2010, Australia
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5
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Verkerk K, van der Wel TJWT, Zeverijn LJ, Geurts BS, Spiekman IAC, de Wit GF, Roepman P, Jansen AML, van der Noort V, Smit EF, Hoeben A, Hendriks LEL, van den Heuvel MM, Piet B, Herder GJM, Hashemi SMS, Gelderblom H, Verheul HMW, Voest EE, de Langen AJ. Safety, Efficacy, and Biomarker Analysis of Crizotinib in MET-Mutated Non-Small Cell Lung Cancer-Results from the Drug Rediscovery Protocol. Clin Cancer Res 2024; 30:5323-5332. [PMID: 39352721 DOI: 10.1158/1078-0432.ccr-24-1925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/26/2024] [Accepted: 09/26/2024] [Indexed: 12/12/2024]
Abstract
PURPOSE To provide patients with MET-mutated advanced non-small cell lung cancer (METmut aNSCLC) access to crizotinib, further substantiate evidence of its efficacy and safety in this setting, and find potential biomarkers for nonresponse. PATIENTS AND METHODS In the Drug Rediscovery Protocol (NCT0295234), patients with an actionable molecular profile are treated with off-label registered drugs. Both treated and untreated patients with aNSCLC harboring MET exon 14 skipping or other MET mutations received crizotinib 250 mg BID until disease progression or intolerable toxicity. Primary endpoints were clinical benefit [CB: RECIST v1.1 confirmed partial response, complete response (CR), or stable disease ≥16 weeks] and safety. Patients were enrolled using a Simon-like two-stage design, with eight patients in stage I and if ≥1/8 patients had CB, 24 patients in stage II. Whole-genome sequencing and RNA sequencing were performed on baseline biopsies. RESULTS Between September 2018 and October 2022, 30 patients started treatment, and 24 were response-evaluable after completing ≥1 full treatment cycle. Two patients (8.3%) achieved CR, 13 (54.2%) partial response, and two (8.3%) stable disease. The CB rate was 70.8% [95% confidence interval (CI), 48.9-87.4], and the objective response rate was 62.5% (95% CI, 40.6-81.2). After 21.2-month median follow-up, median duration of response, progression-free survival, and overall survival were 9.3 (95% CI, 6.5-not available), 10.2 (95% CI, 6.0-20.1), and 13.0 months (95% CI, 9.0-not available), respectively. Twenty-three treatment-related grade ≥ 3 adverse events occurred in 12/30 patients (40%), causing treatment discontinuation in three (10%). One patient (achieving CR) had a tyrosine kinase domain mutation (p.H1094Y), and all other patients had MET exon 14 skipping mutations. CONCLUSIONS Crizotinib is a valuable treatment option in METmut aNSCLC.
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Affiliation(s)
- Karlijn Verkerk
- Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | | | - Laurien J Zeverijn
- Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Birgit S Geurts
- Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Ilse A C Spiekman
- Oncode Institute, Utrecht, the Netherlands
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Gijs F de Wit
- Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Paul Roepman
- Hartwig Medical Foundation, Amsterdam, the Netherlands
| | - Anne M L Jansen
- Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Egbert F Smit
- Department of Pulmonology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ann Hoeben
- Division of Medical Oncology, Department of Internal Medicine, GROW School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Lizza E L Hendriks
- Department of Pulmonology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Michel M van den Heuvel
- Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Berber Piet
- Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Gerarda J M Herder
- Department of Pulmonology, Meander Medical Center, Amersfoort, the Netherlands
| | - Sayed M S Hashemi
- Department of Pulmonary Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Emile E Voest
- Department of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
- Center for Personalized Cancer Treatment, the Netherlands
| | - Adrianus J de Langen
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
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6
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Mer AH, Mirzaei Y, Misamogooe F, Bagheri N, Bazyari A, Keshtkaran Z, Meyfour A, Shahedi A, Amirkhani Z, Jafari A, Barpour N, Jahandideh S, Rezaei B, Nikmanesh Y, Abdollahpour-Alitappeh M. Progress of antibody-drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies. Drug Deliv Transl Res 2024; 14:2963-2988. [PMID: 38597995 DOI: 10.1007/s13346-024-01564-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/29/2024] [Indexed: 04/11/2024]
Abstract
The cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody-drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs.
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Affiliation(s)
- Ali Hussein Mer
- Department of Nursing, Mergasour Technical Institute, Erbil Polytechnic University, Erbil, Iraq
| | - Yousef Mirzaei
- Department of Medical Biochemical Analysis, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Fatemeh Misamogooe
- Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, 8813733450, Iran
| | - Ahmadreza Bazyari
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Keshtkaran
- Department of Nursing, School of Nursing and Midwifery, Community Based Psychiatric Care Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Shahedi
- Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran
| | - Zahra Amirkhani
- Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Barpour
- Department of Genetics, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Saeed Jahandideh
- Department of Research and Development, Orchidgene Co, Tehran, 1387837584, Iran
| | - Behzad Rezaei
- Laparoscopy Research Center, Department of Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars Province, Iran
| | - Yousef Nikmanesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Hungria V, Sureda A, Campelo GR, Salvino MA, Ramasamy K. Proceedings from the First Onco Summit: LATAM Chapter, 19-20 May 2023, Rio de Janeiro, Brazil. Cancers (Basel) 2024; 16:3063. [PMID: 39272921 PMCID: PMC11394439 DOI: 10.3390/cancers16173063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/20/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
The Onco Summit 2023: The Latin American (LATAM) Chapter took place over two days, from 19-20 May 2023, in Brazil. The event aimed to share the latest updates across various oncology disciplines, address critical clinical challenges, and exchange best practices to ensure optimal patient treatment. More than 30 international and regional speakers and more than 300 oncology specialists participated in the Summit. The Summit discussions centered on common challenges and therapeutic advances in cancer care, with a specific focus on the unique obstacles faced in LATAM and examples of adaptable strategies to address these challenges. The Summit also facilitated the establishment of a network of oncologists, hematologists, and scientists in LATAM, enabling collaboration to improve cancer care, both in this region and globally, through drug development and clinical research. This report summarizes the key discussions from the Summit for the global and LATAM oncology community.
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Affiliation(s)
- Vania Hungria
- Hematology, Faculty of Medical Sciences of Santa Casa de São Paulo, São Paulo 01224-001, Brazil
| | - Anna Sureda
- Clinical Hematology Department, Catalan Institut Català d'Oncologia-L'Hospitalet, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), University of Barcelona (UB), 08908 Barcelona, Spain
| | - Garcia Rosario Campelo
- Thoracic Tumors Unit, Medical Oncology Department, University Hospital A Coruña Biomedical Research Institute (INIBIC), 15006 A Coruña, Spain
| | - Marco Aurélio Salvino
- Cell Therapy, D'OR Institute Research & Education (IDOR)/PPGMS-Federal University of Bahia (UFBA), Salvador 40110-100, Brazil
| | - Karthik Ramasamy
- Oxford Translational Myeloma Centre, NDORMS, University of Oxford, Oxford OX3 7LD, UK
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8
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Gou Q, Gou Q, Gan X, Xie Y. Novel therapeutic strategies for rare mutations in non-small cell lung cancer. Sci Rep 2024; 14:10317. [PMID: 38705930 PMCID: PMC11070427 DOI: 10.1038/s41598-024-61087-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 04/30/2024] [Indexed: 05/07/2024] Open
Abstract
Lung cancer is still the leading cause of cancer-related mortality. Over the past two decades, the management of non-small cell lung cancer (NSCLC) has undergone a significant revolution. Since the first identification of activating mutations in the epidermal growth factor receptor (EGFR) gene in 2004, several genetic aberrations, such as anaplastic lymphoma kinase rearrangements (ALK), neurotrophic tropomyosin receptor kinase (NTRK) and hepatocyte growth factor receptor (MET), have been found. With the development of gene sequencing technology, the development of targeted drugs for rare mutations, such as multikinase inhibitors, has provided new strategies for treating lung cancer patients with rare mutations. Patients who harbor this type of oncologic driver might acquire a greater survival benefit from the use of targeted therapy than from the use of chemotherapy and immunotherapy. To date, more new agents and regimens can achieve satisfactory results in patients with NSCLC. In this review, we focus on recent advances and highlight the new approval of molecular targeted therapy for NSCLC patients with rare oncologic drivers.
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Affiliation(s)
- Qitao Gou
- Department of Radiation Oncology and Department of Head & Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qiheng Gou
- Department of Radiation Oncology and Department of Head & Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Xiaochuan Gan
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuxin Xie
- Department of Medical Oncology of Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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9
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Xia S, Duan W, Xu M, Li M, Tang M, Wei S, Lin M, Li E, Liu W, Wang Q. Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET. J Exp Clin Cancer Res 2024; 43:103. [PMID: 38570866 PMCID: PMC10988939 DOI: 10.1186/s13046-024-03015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/18/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. METHODS The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. RESULTS MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. CONCLUSIONS Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.
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Affiliation(s)
- Shengkai Xia
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Wenzhe Duan
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Mingxin Xu
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Mengqi Li
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Mengyi Tang
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Song Wei
- Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Manqing Lin
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Encheng Li
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
| | - Wenwen Liu
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
- Department of Scientific Research Center, The Second Hospital, Dalian Medical University, Dalian, China.
| | - Qi Wang
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
- Department of Scientific Research Center, The Second Hospital, Dalian Medical University, Dalian, China.
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10
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Acharya B, Saha D, Armstrong D, Jabali B, Hanafi M, Herrera-Rueda A, Lakkaniga NR, Frett B. Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with small molecules. RSC Med Chem 2024; 15:399-415. [PMID: 38389874 PMCID: PMC10880908 DOI: 10.1039/d3md00457k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 12/10/2023] [Indexed: 02/24/2024] Open
Abstract
Methods utilized for drug discovery and development within the kinome have rapidly evolved since the approval of imatinib, the first small molecule kinase inhibitor. Macrocycles have received increasing interest as a technique to improve kinase inhibitor drug properties evident by the FDA approvals of lorlatinib, pacritinib, and repotrectinib. Compared to their acyclic counterparts, macrocycles can possess improved pharmacodynamic and pharmacokinetic properties. This review highlights clinical success stories when implementing macrocycles in kinase-based drug discovery and showcases that macrocyclization is a clinically validated drug discovery strategy when targeting the kinome.
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Affiliation(s)
- Baku Acharya
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Debasmita Saha
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
- Conrad Prebys Centre for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute San Diego CA USA
| | - Daniel Armstrong
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Baha'a Jabali
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Maha Hanafi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University Cairo 11526 Egypt
| | - Alan Herrera-Rueda
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
| | - Naga Rajiv Lakkaniga
- Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines) Dhanbad India
| | - Brendan Frett
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA
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11
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Lai WA, Huang YS, Chang KC, Yang SF, Yang CJ, Liu YW, Chen HD. Next-Generation Sequencing in Lung Cancers-A Single-Center Experience in Taiwan. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:236. [PMID: 38399524 PMCID: PMC10890140 DOI: 10.3390/medicina60020236] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/25/2024]
Abstract
Background and Objectives: Lung cancer is a leading cause of cancer mortality in Taiwan. With rapid advancement of targeted therapeutics in non-small cell lung cancers, next-generation sequencing (NGS) is becoming an important tool for biomarker testing. In this study, we describe institutional experience of NGS analysis in non-small cell carcinoma (NSCLC). Materials and Methods: A cohort of 73 cases was identified from the institutional pathology archive in the period between November 2020 and December 2022. Results: Adenocarcinoma was the most common histologic type (91.8%). Most patients presented with stage IIIB and beyond (87.7%). Twenty-nine patients (39.7%) were evaluated at the time of initial diagnosis, while the others had received prior chemotherapy or targeted therapy. The most frequently mutated gene was EGFR (63%), and this was followed by TP53 (50.7%), KRAS (13.7%), RB1 (13.7%), and CDKN2A (13.7%). Clinically actionable mutations associated with a guideline-suggested targeted therapy were identified in 55 cases (75.3%) overall, and in 47.1% of cases excluding EGFR TKI-sensitizing mutation. Biomarkers other than EGFR TKI-sensitizing mutations were compared. Cases without TKI-sensitizing EGFR mutation had more level 1 or 2 biomarkers (excluding EGFR TKI-sensitizing mutations) than cases with TKI-sensitizing EGFR mutations (47.1% versus 20.1%, p = 0.016). Progressive disease was associated with co-occurrence of clinically actionable mutations (20.5% versus 0%, p < 0.05). Eight of the nine cases with co-occurring actionable genetic alternations had an EGFR mutation. After an NGS test, 46.1% of actionable or potentially actionable genetic alternations led to patients receiving a matched therapy. Conclusions: Our study demonstrated that NGS analysis identifies therapeutic targets and may guide treatment strategies in NSCLC. NGS tests may be advantageous over multiple single-gene tests for optimization of treatment plans, especially for those with non-EGFR mutations or those with progressive disease.
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Affiliation(s)
- Wei-An Lai
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.H.)
| | - Yen-Shuo Huang
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.H.)
| | - Kung-Chao Chang
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Pathology, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Sheau-Fang Yang
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.H.)
- Department of Pathology, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chih-Jen Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yu-Wei Liu
- Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Huan-Da Chen
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (Y.-S.H.)
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12
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Zhang P, Wang C, Lv Z, Du M, Xu R. Crizotinib combined with bronchoscopic interventional treatment in ALK-positive inflammatory myofibroblastic tumor of left main stem bronchus: a case report. J Cardiothorac Surg 2023; 18:318. [PMID: 37950305 PMCID: PMC10638830 DOI: 10.1186/s13019-023-02427-7] [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: 05/21/2022] [Accepted: 11/03/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Inflammatory myofibroblastic tumor (IMT), also known as an inflammatory pseudotumor, is a unique type of intermediate soft tissue tumor that commonly occurred in the lung. Its unclear etiology and cellular activity brought about the confusion not only in naming of it, but also in diagnosis and treatment. CASE PRESENTATION We reported the case of an 18-year-old male student who suffered from shortness of breath, chest tightness and chest pain. Chest computed tomography scan showed a spherical neoplasm blocking left main stem bronchus. After fiberoptic bronchoscopy procedure, the results of histopathological and immunohistochemical analysis indicated an IMT. The targeted next generation sequencing based genomic profiling of the tumor using formalin-fixed and paraffin embedded tissue was performed and a EML4-ALK fusion was detected. The patient began to receive Crizotinib, a ALK tyrosine kinase inhibitor, at a dose of 250 mg twice daily orally. The patient has recovered well after the operation, and no recurrence or metastasis has been found after 12 months' follow-up. CONCLUSION By means of the diagnosis and treatment of this case, the characteristics and therapies of IMT are illustrated. In addition, it also provides a reference for the therapeutic strategy of IMT in the future.
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Affiliation(s)
- Peng Zhang
- Department of Cardiothoracic Surgery, The 961st Hospital of Joint Logistics Support Force of PLA, Qiqihar, 230200, China
| | - Chenchen Wang
- Department of Emergency and Critical Care Medicine, The 961st Hospital of Joint Logistics Support Force of PLA, Qiqihar, 230200, China
| | - Zechao Lv
- Department of Pathology, Changzheng Hospital, Naval Medical University, Shanghai, 200040, China
| | - Mingxiang Du
- Department of Cardiothoracic Surgery, The 961st Hospital of Joint Logistics Support Force of PLA, Qiqihar, 230200, China
| | - Ruixin Xu
- Department of Cardiothoracic Surgery, The 960th Hospital of Joint Logistics Support Force of PLA, No. 25 Shifan Road, Tianqiao District, Jinan, 250031, People's Republic of China.
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13
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Shiraishi T, Yamasaki K, Kidogawa M, Shingu T, Ujimiya F, Jotatsu T, Matsumoto S, Izumi H, Nishida C, Goto K, Yatera K. Successful Treatment with Crizotinib to Overcome Drug Resistance Possibly Due to Mesenchymal-epithelial Transition Amplification in a Lung Cancer Patient with the Echinoderm Microtubule-associated Protein-like 4-anaplastic Lymphoma Kinase Fusion Gene. Intern Med 2023; 62:3215-3221. [PMID: 36927974 PMCID: PMC10686730 DOI: 10.2169/internalmedicine.1164-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/11/2023] [Indexed: 03/15/2023] Open
Abstract
Amplification of the mesenchymal-epithelial transition (MET) gene plays an important role in anticancer drug resistance to anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged lung cancer cells. We encountered an ALK-rearranged lung cancer patient who developed MET amplification after alectinib treatment and showed an effective response to fifth-line crizotinib. First-line alectinib treatment was effective for 2.5 years; however, liver metastases exacerbated. Liver biopsy specimens revealed MET and human epidermal growth factor receptor 2 (HER2) amplifications. Switching to the MET inhibitor crizotinib improved liver metastases. Crizotinib may be effective in ALK-positive patients with MET amplification.
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Affiliation(s)
- Tomoko Shiraishi
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Kei Yamasaki
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Moe Kidogawa
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Tatsuya Shingu
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Fuki Ujimiya
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Takanobu Jotatsu
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Shingo Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Japan
| | - Hiroki Izumi
- Department of Thoracic Oncology, National Cancer Center Hospital East, Japan
| | - Chinatsu Nishida
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
| | - Koichi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Japan
| | - Kazuhiro Yatera
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan
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Spitaleri G, Trillo Aliaga P, Attili I, Del Signore E, Corvaja C, Corti C, Uliano J, Passaro A, de Marinis F. MET in Non-Small-Cell Lung Cancer (NSCLC): Cross 'a Long and Winding Road' Looking for a Target. Cancers (Basel) 2023; 15:4779. [PMID: 37835473 PMCID: PMC10571577 DOI: 10.3390/cancers15194779] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the 'druggable' molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.
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Affiliation(s)
- Gianluca Spitaleri
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
| | - Pamela Trillo Aliaga
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
| | - Ilaria Attili
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
| | - Ester Del Signore
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
| | - Carla Corvaja
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
| | - Chiara Corti
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (C.C.); (J.U.)
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Jacopo Uliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (C.C.); (J.U.)
- Department of Oncology and Haematology (DIPO), University of Milan, 20122 Milan, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
| | - Filippo de Marinis
- Division of Thoracic Oncology, IEO, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, Italy; (P.T.A.); (I.A.); (E.D.S.); (C.C.); (F.d.M.)
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15
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Wang C, Lu X. Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy. J Med Chem 2023. [PMID: 37262349 DOI: 10.1021/acs.jmedchem.3c00028] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.
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Affiliation(s)
- Chaofan Wang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China
| | - Xiaoyun Lu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China
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16
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Tang M, Li X, Zhang Y, Li H, Zhao C, Zhao M, Wang Y, Jiang C, Su F. Effective treatment of MET-amplified non-small cell lung cancer patients with crizotinib: a case description. Quant Imaging Med Surg 2023; 13:3351-3356. [PMID: 37179908 PMCID: PMC10167464 DOI: 10.21037/qims-22-997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 03/10/2023] [Indexed: 03/29/2023]
Affiliation(s)
- Mingyue Tang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Xinwei Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yue Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Huiyuan Li
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Cancan Zhao
- Department of Radiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Menglin Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yanyan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- Department of Internal Medicine, Foshan First People’s Hospital, Foshan, China
| | - Chenchen Jiang
- Cancer Neurobiology Group, School of Biomedical Sciences & Pharmacy, The University of Newcastle, Callaghan, NSW, Australia
| | - Fang Su
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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17
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He S, He P, Wu H, Feng Y, Situ J, Chen Y, Du J, Qin J, Lv P, Chen K. Design, Synthesis and Biological Evaluation of Multi-Target Anti-Cancer Agent PYR26. Int J Mol Sci 2023; 24:ijms24087131. [PMID: 37108294 PMCID: PMC10138507 DOI: 10.3390/ijms24087131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 04/29/2023] Open
Abstract
This study investigates the synthesis of a new compound, PYR26, and the multi-target mechanism of PYR26 inhibiting the proliferation of HepG2 human hepatocellular carcinoma cells. PYR26 significantly inhibits the growth of HepG2 cells (p < 0.0001) and this inhibition has a concentration effect. There was no significant change in ROS release from HepG2 cells after PYR26 treatment. The mRNA expressions of CDK4, c-Met and Bak genes in HepG2 cells were significantly inhibited (p < 0.05), while mRNA expression of pro-apoptotic factors such as caspase-3 and Cyt c was significantly increased (p < 0.01). The expression of PI3K, CDK4 and pERK proteins decreased. The expression level of caspase-3 protein was increased. PI3K is a kind of intracellular phosphatidylinositol kinase. PI3K signaling pathway is involved in signal transduction of a variety of growth factors, cytokines and extracellular matrix and plays an important role in preventing cell apoptosis, promoting cell survival and influencing cell glucose metabolism. CDK4 is a catalytic subunit of the protein kinase complex and is important for G1 phase progression of the cell cycle. PERK refers to phosphorylated activated ERK, which is translocated from cytoplasm to the nucleus after activation, and then participates in various biological reactions such as cell proliferation and differentiation, cell morphology maintenance, cytoskeleton construction, cell apoptosis and cell canceration. Compared with the model group and the positive control group, the tumor volume of the nude mice in the low-concentration PYR26 group, the medium-concentration group and the high-concentration group was smaller, and the organ volume was smaller than that in the model group and the positive control group. The tumor inhibition rates of low-concentration group PYR26, medium-concentration group and high-concentration group reached 50.46%, 80.66% and 74.59%, respectively. The results showed that PYR26 inhibited the proliferation of HepG2 cells and induced apoptosis of HepG2 cells by down-regulating c-Met, CDK4 and Bak, up-regulating the mRNA expression of caspase-3 and Cyt c genes, down-regulating PI3K, pERK and CDK4 proteins and up-regulating the protein level of caspase-3. In a certain range, with the increase in PYR26 concentration, the tumor growth was slower and the tumor volume was smaller. Preliminary results showed that PYR26 also had an inhibitory effect on the tumors of Hepa1-6 tumor-bearing mice. These results suggest that PYR26 has an inhibitory effect on the growth of liver cancer cells, therefore it has potential to be developed into a new anti-liver cancer drug.
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Affiliation(s)
- Sirong He
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Peiting He
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Haojing Wu
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Yao Feng
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Jiejin Situ
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Yiling Chen
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Junxi Du
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Jin Qin
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Pengcheng Lv
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
| | - Kun Chen
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou 510006, China
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18
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MET Exon 14 Variants in Non-Small Cell Lung Carcinoma: Prevalence, Clinicopathologic and Molecular Features. JOURNAL OF MOLECULAR PATHOLOGY 2023. [DOI: 10.3390/jmp4010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
Somatic MET exon 14 skipping mutations (MET ex14) are targetable driver mutations for non-small cell lung cancer (NSCLC), responsive to MET inhibitors. Objective: This study seeks to further characterize the clinicopathologic features and mutational profile of MET ex14 variant NSCLC. Design: Retrospective review of all MET ex14 tested NSCLC. Testing for selected BRAF, EGFR, HER2, KRAS, and MET mutations was performed using a clinically validated NGS assay, followed by MiSeq sequencing. Variants were classified as significant (Tier1/2) or variants of uncertain significance (VUS) per 2017 AMP/ASCO/CAP Joint Consensus Guidelines. PD-L1 expression was assessed by immunohistochemistry. Results: Of 2296 NSCLCs tested between 2017-7/2019, MET ex14 variants were present in 44 (1.9%). A total of 32 of 44 variants were MET exon 14 skipping, while the other 12 mutations were significant missense (3) or VUS (9). Of nine VUS, five were adjacent to the canonical splice site and likely to impact splicing. Four cases had concomitant mutations. Of 35 cases with known clinical staging, stage 1–2 = 20 (57%), stage 3 = 3 (9%), and stage 4 = 12 (34%). Of 19 resected NSCLSs, histological types and growth pattern included 7 lepidic pattern-predominant. A high percentage of tumors with MET ex14 mutations are positive for PD-L1, and the percentage of cases with PD-L1 expression >50% trends higher in more advanced disease. Conclusions: Most MET variants identified in our cohort (73%) are MET ex14 skipping. The prevalence of MET ex14 variants is 1.9%, and a large percentage of tumors has lower clinical stage and less aggressive pathologic features.
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Nigro MC, Marchese PV, Deiana C, Casadio C, Galvani L, Di Federico A, De Giglio A. Clinical Utility and Application of Liquid Biopsy Genotyping in Lung Cancer: A Comprehensive Review. LUNG CANCER (AUCKLAND, N.Z.) 2023; 14:11-25. [PMID: 36762267 PMCID: PMC9904307 DOI: 10.2147/lctt.s388047] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 01/26/2023] [Indexed: 02/05/2023]
Abstract
Precision medicine has revolutionized the therapeutic management of cancer patients with a major impact on non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, where advances have been remarkable. Tissue biopsy, required for tumor molecular testing, has significant limitations due to the difficulty of the biopsy site or the inadequacy of the histological specimen. In this context, liquid biopsy, consisting of the analysis of tumor-released materials circulating in body fluids, such as blood, is increasingly emerging as a valuable and non-invasive biomarker for detecting circulating tumor DNA (ctDNA) carrying molecular tumor signatures. In advanced/metastatic NSCLC, liquid biopsy drives target therapy by monitoring response to treatment and identifying eventual genomic mechanisms of resistance. In addition, recent data have shown a significant ability to detect minimal residual disease in early-stage lung cancer, underlying the potential application of liquid biopsy in the adjuvant setting, in early detection of recurrence, and also in the screening field. In this article, we present a review of the currently available data about the utility and application of liquid biopsy in lung cancer, with a particular focus on the approach to different techniques of analysis for liquid biopsy and a comparison with tissue samples as well as the potential practical uses in early and advanced/metastatic NSCLC.
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Affiliation(s)
- Maria Concetta Nigro
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy
| | - Paola Valeria Marchese
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy,Correspondence: Paola Valeria Marchese, Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Via Albertoni 15, Bologna, 40138, Italy, Email
| | - Chiara Deiana
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy
| | - Chiara Casadio
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy
| | - Linda Galvani
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy
| | - Alessandro Di Federico
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy
| | - Andrea De Giglio
- Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, University of Bologna, Bologna, 40138, Italy,Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, 40138, Italy
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20
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Peng Y, Zhang W, Chen Y, Zhang L, Shen H, Wang Z, Tian S, Yang X, Cui D, He Y, Chang X, Feng Z, Tang Q, Mao Y. Engineering c-Met-CAR NK-92 cells as a promising therapeutic candidate for lung adenocarcinoma. Pharmacol Res 2023; 188:106656. [PMID: 36640859 DOI: 10.1016/j.phrs.2023.106656] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/31/2022] [Accepted: 01/10/2023] [Indexed: 01/13/2023]
Abstract
Mesenchymal-epithelial transition factor (C-Met) has been acknowledged as a significant therapeutic target for treating lung adenocarcinoma (LUAD). However, the potential application of chimeric antigen receptors (CAR)-modified natural killer (NK) cells targeting c-Met in LUAD is rarely explored. In this study, bioinformatic databases were searched and a tissue microarray (TMA) was enrolled to investigate expression status and prognostic role of c-Met in LUAD. Then, four types of c-Met-CAR structures were designed and prepared. The engineering CAR-NK cells containing c-Met-CARs were transfected, verified and characterized. The tumor-inhibitory role of c-Met-CAR-NK cells was finally evaluated in vitro and in vivo. The results demonstrated that c-Met expression elevated and confirmed that high c-Met expression was significantly associated with unfavorable prognosis in LUAD. Then, C-Met-CAR-NK cells were successfully constructed and DAP10 designed in CAR structure was a favorable stimulator for NK cell activation. CCN4 containing DAP10 co-stimulator exhibited the strongest cytotoxicity compared with other CAR-NK cells. Furthermore, CCN4 cells also exerted the prominent tumor-inhibitory effect on xenograft tumor growth. Collectively, this study suggests that DAP10 is a potent stimulator in CAR structure for NK cell activation, and CCN4-based immunotherapy may represent a promising strategy for the treatment of c-Met-positive LUAD.
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Affiliation(s)
- Yan Peng
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Wenqing Zhang
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Yufeng Chen
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Louqian Zhang
- Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hongyu Shen
- Gusu School, Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zheyue Wang
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Shuning Tian
- Department of Obstetrics and Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Xiaohui Yang
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Daixun Cui
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Yiting He
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Xinxia Chang
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China
| | - Zhenqing Feng
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China; Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
| | - Qi Tang
- National Health Commission Key Laboratory of Antibody Techniques, Nanjing Medical University, Nanjing, China; Department of Pathology, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing, China.
| | - Yuan Mao
- Department of Oncology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China; Department of Oncology, Geriatric Hospital of Nanjing Medical University, Nanjing, China.
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21
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Martinelli I, Modica C, Chiriaco C, Basilico C, Hughes JM, Corso S, Giordano S, Comoglio PM, Vigna E. hOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers. J Exp Clin Cancer Res 2022; 41:112. [PMID: 35351166 PMCID: PMC8962049 DOI: 10.1186/s13046-022-02320-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 03/09/2022] [Indexed: 12/21/2022] Open
Abstract
Background The tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition. Methods Here we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed. Results hOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys. Conclusions hOA-DN30 unique ability to simultaneously erase cell surface MET and release the ‘decoy’ receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02320-6.
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22
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Bang TJ, Hu J, Patil T, Barón AE, Gao D, Yang JCH, Kuo HY, Huang HC, Sachs PB, Camidge DR. The Effect of Intrathoracic Lesion Location on Initial Tyrosine Kinase Inhibitor Response in Advanced Oncogene-Addicted Non-Small Cell Lung Cancer: A Comparison Between RECIST 1.1 and a Novel Method of Response Assessment (MAX). Clin Lung Cancer 2022; 23:e501-e509. [PMID: 36100512 DOI: 10.1016/j.cllc.2022.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/25/2022] [Accepted: 08/03/2022] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Different subtypes of non-small cell lung cancer (NSCLC) are associated with different patterns of metastatic spread. Anatomic location of lesions in the chest may influence patterns of cancer growth and the shrinkage to therapy. Consequently, lesion location could affect apparent response rates per RECIST. We sought to explore this and develop, as needed, treatment response assessments less affected by the location. METHODS Cases of advanced oncogene-addicted NSCLC (EGFR, ALK, and ROS1) with pre- and on-therapy imaging during initial targeted therapy were identified. Lesions located in the lung parenchyma, pleural space or intra-thoracic lymph nodes were identified and analyzed separately from each other by RECIST 1.1 (unidimensional measurements) and by a novel MAX methodology (bidimensional measurements) which takes the axis with the greatest absolute percentage change on therapy in each location as the representative measurement. RESULTS Three hundred three patients with 446 unidimensional measured lesions were included for RECIST analysis. Two hundred forty nine patients with 386 bidimensional measured lesions were included for MAX analysis, as well as the analysis comparing RECIST and MAX. Intrathoracic location significantly impacted percentage shrinkage and the response rate per RECIST. The response rates for pleural, intra-parenchymal and nodal lesions were 34.1%, 49.6%, and 68.3%, respectively (P = .0002). The MAX methodology both increased the apparent treatment effect and made it consistent between intrathoracic locations. For pleural, parenchymal and nodal lesions, the MAX calculated response rate were 83.7%, 72.2%, and 75.4%, respectively (P-value = .24). CONCLUSION Intrathoracic lesion location affects RECIST-based treatment effectiveness estimations. The MAX methodology neutralizes location effect when examining impact of treatment and should be explored further.
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Affiliation(s)
- Tami J Bang
- Division of Cardiothoracic Imaging, Department of Radiology, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Junxiao Hu
- Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO; University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Tejas Patil
- Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Anna E Barón
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - Dexiang Gao
- Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO; University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - James Chih-Hsin Yang
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Hung-Yang Kuo
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Hsin-Chieh Huang
- Department of Radiology, National Taiwan University Hospital, Taipei, Taiwan
| | - Peter B Sachs
- Division of Cardiothoracic Imaging, Department of Radiology, University of Colorado, Anschutz Medical Campus, Aurora, CO
| | - D Ross Camidge
- Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO.
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23
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Laktionov KK, Artamonova EV, Borisova TN, Breder VV, Bychkov IM, Vladimirova LI, Volkov NM, Ergnian SM, Zhabina AS, Kononets PV, Kuzminov AE, Levchenko EV, Malikhova OA, Marinov DT, Miller SV, Moiseenko FV, Mochal’nikova VV, Novikov SN, Pikin OV, Reutova EV, Rodionov EO, Sakaeva DD, Sarantseva KA, Semenova AI, Smolin AV, Sotnikov VM, Tuzikov SA, Turkin IN, Tyurin IE, Chkhikvadze VD, Kolbanov KI, Chernykh MV, Chernichenko AV, Fedenko AA, Filonenko EV, Nevol’skikh AA, Ivanov SA, Khailova ZV, Gevorkian TG, Butenko AV, Gil’mutdinova IR, Gridneva IV, Eremushkin MA, Zernova MA, Kasparov BS, Kovlen DV, Kondrat’eva KO, Konchugova TV, Korotkova SB, Krutov AA, Obukhova OA, Ponomarenko GN, Semiglazova TI, Stepanova AM, Khulamkhanova MM. Malignant neoplasm of the bronchi and lung: Russian clinical guidelines. JOURNAL OF MODERN ONCOLOGY 2022. [DOI: 10.26442/18151434.2022.3.201848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
удалить
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24
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Solomon JP, Yang SR, Choudhury NJ, Ptashkin RN, Eslamdoost N, Falcon CJ, Martin A, Plodkowski A, Wilhelm C, Shen R, Ladanyi M, Berger M, Zhang Y, Drilon A, Arcila ME. Bioinformatically Expanded Next-Generation Sequencing Analysis Optimizes Identification of Therapeutically Relevant MET Copy Number Alterations in >50,000 Tumors. Clin Cancer Res 2022; 28:4649-4659. [PMID: 36044468 PMCID: PMC9633455 DOI: 10.1158/1078-0432.ccr-22-1321] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 07/07/2022] [Accepted: 08/29/2022] [Indexed: 01/24/2023]
Abstract
PURPOSE Clinical relevance thresholds and laboratory methods are poorly defined for MET amplification, a targetable biomarker across malignancies. EXPERIMENTAL DESIGN The utility of next-generation sequencing (NGS) in assessing MET copy number alterations was determined in >50,000 solid tumors. Using fluorescence in situ hybridization as reference, we validated and optimized NGS analysis. RESULTS Incorporating read-depth and focality analyses achieved 91% concordance, 97% sensitivity, and 89% specificity. Tumor heterogeneity, neoplastic cell proportions, and genomic focality affected MET amplification assessment. NGS methodology showed superiority in capturing overall amplification status in heterogeneous tumors and defining amplification focality among other genomic alterations. MET copy gains and amplifications were found in 408 samples across 23 malignancies. Total MET copy number inversely correlated with amplified segment size. High-level/focal amplification was enriched in certain genomic subgroups and associated with targeted therapy response. CONCLUSIONS Leveraging our integrated bioinformatic approach, targeted therapy benefit was observed across diverse MET amplification contexts.
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Affiliation(s)
- James P. Solomon
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Soo-Ryum Yang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Noura J. Choudhury
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ryan N. Ptashkin
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nasrin Eslamdoost
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Christina J. Falcon
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Axel Martin
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrew Plodkowski
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Clare Wilhelm
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronglai Shen
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Berger
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yanming Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander Drilon
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria E. Arcila
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,Correspondence: Maria E. Arcila, Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Phone: 212-639-7879;
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25
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Chiriaco C, Donini C, Cortese M, Ughetto S, Modica C, Martinelli I, Proment A, Vitali L, Fontani L, Casucci M, Comoglio PM, Giordano S, Sangiolo D, Leuci V, Vigna E. Efficacy of CAR-T immunotherapy in MET overexpressing tumors not eligible for anti-MET targeted therapy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:309. [PMID: 36271379 PMCID: PMC9585715 DOI: 10.1186/s13046-022-02479-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/30/2022] [Indexed: 11/07/2022]
Abstract
Background Aberrant activation of the MET receptor in cancer is sustained by genetic alterations or, more frequently, by transcriptional upregulations. A fraction of MET-amplified or mutated tumors are sensible to MET targeting agents, but their responsiveness is typically short-lasting, as secondary resistance eventually occurs. Since in the absence of genetic alterations MET is usually not a tumor driver, MET overexpressing tumors are not/poorly responsive to MET targeted therapies. Consequently, the vast majority of tumors exhibiting MET activation still represent an unmet medical need. Methods Here we propose an immunotherapy strategy based on T lymphocytes expressing a Chimeric Antigen Receptor (CAR) targeting MET overexpressing tumors of different histotypes. We engineered two different MET-CAR constructs and tested MET-CAR-T cell cytotoxic activity against different MET overexpressing models, including tumor cell lines, primary cancer cells, organoids, and xenografts in immune-deficient mice. Results We proved that MET-CAR-T exerted a specific cytotoxic activity against MET expressing cells. Cell killing was proportional to the level of MET expressed on the cell surface. While CAR-T cytotoxicity was minimal versus cells carrying MET at physiological levels, essentially sparing normal cells, the activity versus MET overexpressing tumors was robust, significantly controlling tumor cell growth in vitro and in vivo. Notably, MET-CAR-T cells were also able to brake acquired resistance to MET targeting agents in MET amplified cancer cells carrying secondary mutations in downstream signal transducers. Conclusions We set and validated at the pre-clinical level a MET-CAR immunotherapy strategy potentially beneficial for cancers not eligible for MET targeted therapy with inhibitory molecules, including those exhibiting primary or secondary resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02479-y.
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Affiliation(s)
- Cristina Chiriaco
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,Present address: Anemocyte S.r.l., 21040 Gerenzano, VA Italy
| | - Chiara Donini
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
| | - Marco Cortese
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
| | - Stefano Ughetto
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy ,Present address: Bios-Therapy, Physiological System for Health S.p.A, 52037 Sansepolcro, AR Italy
| | - Chiara Modica
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.10776.370000 0004 1762 5517Present address: Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Ilaria Martinelli
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy
| | - Alessia Proment
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
| | - Letizia Vitali
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
| | - Lara Fontani
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy
| | - Monica Casucci
- grid.18887.3e0000000417581884Innovative Immunotherapies Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Maria Comoglio
- grid.7678.e0000 0004 1757 7797IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
| | - Silvia Giordano
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
| | - Dario Sangiolo
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
| | - Valeria Leuci
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy
| | - Elisa Vigna
- grid.419555.90000 0004 1759 7675Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, 10060 Candiolo, TO Italy ,grid.7605.40000 0001 2336 6580Department of Oncology, University of Turin, Turin, Italy
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26
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Nie Y, Feng F, Luo W, Sanders AJ, Zhang Y, Liang J, Chen C, Feng W, Gu W, Liao W, Wang W, Chen J, Zhang L, Jiang WG, Li J. Overexpressed transient receptor potential vanilloid 1 (TRPV1) in lung adenocarcinoma harbours a new opportunity for therapeutic targeting. Cancer Gene Ther 2022; 29:1405-1417. [PMID: 35354949 PMCID: PMC9576597 DOI: 10.1038/s41417-022-00459-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/26/2022] [Accepted: 03/09/2022] [Indexed: 12/12/2022]
Abstract
The specific biological function of transient receptor potential vanilloid 1 (TRPV1) in pathogenesis of lung adenocarcinoma (LUAD) remains unclear. In this study, TRPV1 expression in tumor tissues, primary cells and cell lines of LUAD, as well as the mechanism mediating its hyperexpression were systematically studied. Multiple models and techniques were adopted to elucidate the relationship between TRPV1 hyperexpression and tumor recurrence and metastasis. Results showed that TRPV1 expression was increased in tumor tissues and primary tumor cells of LUAD patients. The increased expression was associated with worse overall survival outcome and raised HIF1α levels. TRPV1 expression in A549 and NCI-H292 cells was increased after pretreatment with cigarette smoke extract or spermine NONOate. Moreover, A549 cells with TRPV1 overexpression has enhanced tumor growth rates in subcutaneous grafted tumor models, and increased intrapulmonary metastasis after tail vein infusion in nude BALB/c nude mice. Mechanistically, TRPV1 overexpression in A549 cells promoted HIF1α expression and nuclear translocation by promoting CREB phosphorylation and activation of NOS1-NO pathway, ultimately leading to accelerated cell proliferation and stronger invasiveness. In addition, based on photothermal effects, CuS-TRPV1 mAb effectively targeted and induced apoptosis of TRPV1-A549 cells both in vivo and in vitro, thereby mitigating tumor growth and metastasis induced by xenotransplantation of TRPV1-A549 cells. In conclusion, TRPV1 hyperexpression in LUAD is a risk factor for tumor progression and is involved in proliferation and migration of tumor cells through activation of HIF1α. Our study also attempted a new strategy inhibiting the recurrence and metastasis of LUAD: by CuS-TRPV1 mAb precisely kill TRPV1 hyperexpression cells through photothermal effects.
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Affiliation(s)
- Yichu Nie
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-sen University Foshan Hospital, Foshan, 528000, PR China
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Fenglan Feng
- State Key Laboratory of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, PR China
| | - Wei Luo
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-sen University Foshan Hospital, Foshan, 528000, PR China
| | | | - Yidi Zhang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, 510275, PR China
| | - Jiaming Liang
- State Key Laboratory of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, PR China
| | - Cheng Chen
- State Key Laboratory of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, PR China
| | - Weineng Feng
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-sen University Foshan Hospital, Foshan, 528000, PR China
| | - Weiquan Gu
- Clinical Research Institute, The First People's Hospital of Foshan & Sun Yat-sen University Foshan Hospital, Foshan, 528000, PR China
| | - Weiping Liao
- Foshan Fourth People's Hospital, Foshan, 528000, PR China
| | - Wei Wang
- Foshan Fourth People's Hospital, Foshan, 528000, PR China
| | - Jinfeng Chen
- Peking University Cancer Hospital and Beijing Cancer Institute, Department of Thoracic Surgery, Fucheng Road, Haidian District, Beijing, China
| | - Lijian Zhang
- Peking University Cancer Hospital and Beijing Cancer Institute, Department of Thoracic Surgery, Fucheng Road, Haidian District, Beijing, China
| | - Wen G Jiang
- CCMRC, Cardiff University School of Medicine, Cardiff, UK
| | - Jin Li
- State Key Laboratory of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510120, PR China.
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27
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Sakashita T, Yanagitani N, Koike S, Low SK, Takagi S, Baba S, Takeuchi K, Nishio M, Fujita N, Katayama R. Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer. Cancer Sci 2022; 113:3888-3900. [PMID: 35950895 PMCID: PMC9633314 DOI: 10.1111/cas.15529] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/14/2022] [Accepted: 07/29/2022] [Indexed: 11/28/2022] Open
Abstract
The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%‐5% of patients with non–small cell lung cancer (NSCLC) and confers sensitivity to ALK–tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK‐rearranged NSCLC, various additional ALK‐TKIs have been developed. Ceritinib is a second‐generation ALK‐TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first‐generation ALK‐TKI)‐refractory ALK‐rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib‐resistant, echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK–positive H3122 cells and ceritinib‐resistant patient‐derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib‐resistant patient‐derived specimens confirmed that tyrosine‐protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms.
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Affiliation(s)
- Takuya Sakashita
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN.,Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, JAPAN.,AstraZeneca K.K., Osaka, JAPAN
| | - Noriko Yanagitani
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Sumie Koike
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Siew-Kee Low
- Cancer Precision Medicine Center, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoshi Takagi
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Satoko Baba
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Pathology Project for Molecular Targets, the Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, JAPAN
| | - Kengo Takeuchi
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.,Pathology Project for Molecular Targets, the Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, JAPAN.,Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Naoya Fujita
- Director, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN
| | - Ryohei Katayama
- Div. of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN.,Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, JAPAN
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Park S, Cho EA, Chun JN, Lee DY, Lee S, Kim MY, Bae SM, Jo SI, Lee SH, Park HH, Kim TM, So I, Kim SY, Jeon JH. Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells. Exp Mol Med 2022; 54:1225-1235. [PMID: 35999455 PMCID: PMC9440021 DOI: 10.1038/s12276-022-00835-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/09/2022] [Accepted: 06/16/2022] [Indexed: 12/03/2022] Open
Abstract
Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFβ signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFβ receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFβ- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations.
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Affiliation(s)
- Soonbum Park
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Eun A Cho
- ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Korea
- Department of Medical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jung Nyeo Chun
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Korea
| | - Da Young Lee
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Sanghoon Lee
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Mi Yeon Kim
- ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Korea
- Department of Medical Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sang Mun Bae
- ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Korea
| | - Su In Jo
- ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Korea
| | - So Hee Lee
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Ho Park
- College of Pharmacy, Chung-Ang University, Seoul, Korea
| | - Tae Min Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Insuk So
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Korea
| | - Sang-Yeob Kim
- ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Korea.
| | - Ju-Hong Jeon
- Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
- Institute of Human-Environment Interface Biology, Seoul National University, Seoul, Korea.
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Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer. Cancers (Basel) 2022; 14:cancers14143452. [PMID: 35884511 PMCID: PMC9325236 DOI: 10.3390/cancers14143452] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/12/2022] [Accepted: 07/12/2022] [Indexed: 02/01/2023] Open
Abstract
EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.
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MET Expression Level in Lung Adenocarcinoma Loosely Correlates with MET Copy Number Gain/Amplification and Is a Poor Predictor of Patient Outcome. Cancers (Basel) 2022; 14:cancers14102433. [PMID: 35626038 PMCID: PMC9139916 DOI: 10.3390/cancers14102433] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/02/2022] [Accepted: 05/13/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary MET is a proto-oncogene and plays an important role on tumor cell survival, proliferation, metastasis, and drug resistance. Patient with MET amplification has shown an inferior outcome comparing to patients without MET amplification. Fluorescence in situ hybridization (FISH) is often used to detect MET amplification, and immunohistochemistry (IHC) is often used to assess MET expression level. Though some institutions provide both tests, IHC is more readily available in most pathology laboratories and is cheaper than FISH. This study evaluated the correlation of MET expression level with MET copy number gain/amplification, and the MET overexpression with patient’s outcome. By studying 446 patients with lung adenocarcinoma, we found that the concordance of MET expression and MET copy number gain/amplification was low; high-level of MET expression was associated with inferior outcome, but it was not an independent poor prognostic factor. These findings indicate that IHC for MET expression can’t substitute FISH analysis for MET amplification. Abstract MET amplification has been associated with shorter survival in cancer patients, however, the potential correlation of MET overexpression with either MET amplification or patient outcome is controversial. The aim of this study was to address these questions by correlating MET expression level with MET copy number and patient outcome in a cohort of 446 patients who had a lung adenocarcinoma: 88 with MET amplification, 118 with polysomy 7, and 240 with negative results by fluorescence in situ hybridization. MET expression assessed by immunohistochemistry was semi-quantified by expression level: absent (0+), weak (1+), moderate (2+) and strong (3+); or by H-score: 0–99, 100–199, and ≥200. MET expression level or H-score was positively but weakly correlated with MET copy number or MET/CEP7 ratio. Strong expression of MET (3+ or H-score ≥ 200) was associated with a shorter overall survival, but it was not an independent hazard for survival by multivariant analysis. We conclude that MET expression is loosely correlated with MET copy number gain/amplification. Strong expression of MET does not independently predict patient outcome.
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Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, D'Amico TA, DeCamp M, Dilling TJ, Dowell J, Gettinger S, Grotz TE, Gubens MA, Hegde A, Lackner RP, Lanuti M, Lin J, Loo BW, Lovly CM, Maldonado F, Massarelli E, Morgensztern D, Ng T, Otterson GA, Pacheco JM, Patel SP, Riely GJ, Riess J, Schild SE, Shapiro TA, Singh AP, Stevenson J, Tam A, Tanvetyanon T, Yanagawa J, Yang SC, Yau E, Gregory K, Hughes M. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:497-530. [PMID: 35545176 DOI: 10.6004/jnccn.2022.0025] [Citation(s) in RCA: 806] [Impact Index Per Article: 268.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.
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Affiliation(s)
| | - Douglas E Wood
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | - Ankit Bharat
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Debora S Bruno
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Joe Y Chang
- The University of Texas MD Anderson Cancer Center
| | | | | | | | | | | | | | | | | | | | | | | | - Jules Lin
- University of Michigan Rogel Cancer Center
| | | | | | | | | | - Daniel Morgensztern
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Thomas Ng
- The University of Tennessee Health Science Center
| | - Gregory A Otterson
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | | | | | | | | | - Aditi P Singh
- Abramson Cancer Center at the University of Pennsylvania
| | - James Stevenson
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Alda Tam
- The University of Texas MD Anderson Cancer Center
| | | | | | - Stephen C Yang
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | - Edwin Yau
- Roswell Park Comprehensive Cancer Center; and
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Abdallah HM, Martinez-Meehan D, Lutfi W, Dhupar R, Grenda T, Schuchert MJ, Christie NA, Luketich JD, Okusanya OT. Adjuvant chemotherapy for pulmonary sarcomatoid carcinoma: A retrospective analysis of the National Cancer Database. J Thorac Cardiovasc Surg 2022; 163:1669-1681.e3. [PMID: 33678508 DOI: 10.1016/j.jtcvs.2021.01.081] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 01/15/2021] [Accepted: 01/21/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Pulmonary sarcomatoid carcinoma (PSC) is a rarely occurring variant of non-small cell lung cancer with sarcoma-like features. Compared with traditional non-small cell lung cancer, PSC patients typically present later and have poorer prognoses, irrespective of stage. The standard of care is resection, but guidelines for the use of adjuvant chemotherapy have not been established. To advance the development of evidence-based management algorithms for PSC after resection, a statistical analysis on a nationwide representative sample of patients was performed. METHODS A retrospective cohort study was performed by querying the National Cancer Database for patients with a diagnosis of PSC between 2004 and 2015. Patients who received complete anatomical resection with or without adjuvant chemotherapy were included. Multivariable regression was used to detect factors associated with the receipt of adjuvant chemotherapy. Multivariable Cox regression of overall survival and Kaplan-Meier survival analysis on propensity-matched groups was conducted to study the association between adjuvant chemotherapy and prognosis. RESULTS We included 1497 patients with PSC in the final analysis. Factors associated with receiving adjuvant chemotherapy were age, histology, and receipt of adjuvant radiation. The results of multivariable Cox analysis and Kaplan-Meier analysis on propensity matched groups yielded similar trends: adjuvant chemotherapy was associated with improved 5-year overall survival for stage II and III disease, but not for stage I disease. CONCLUSIONS Multiple factors are associated with receipt of adjuvant chemotherapy for PSC, and this treatment appears to be associated with improved survival in stage II and stage III, but not stage I patients.
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Affiliation(s)
| | | | - Waseem Lutfi
- Department of Surgery, Penn Medicine, Philadelphia, Pa
| | - Rajeev Dhupar
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa; Surgical Services Division, VA Pittsburgh Healthcare System, Pittsburgh, Pa
| | - Tyler Grenda
- Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pa
| | - Matthew J Schuchert
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Neil A Christie
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - James D Luketich
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pa
| | - Olugbenga T Okusanya
- Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pa.
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Hamilton G, Rath B. Met inhibitors in the treatment of lung cancer: the evidence to date. Expert Opin Pharmacother 2022; 23:815-825. [PMID: 35377279 DOI: 10.1080/14656566.2022.2062227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : The hepatocyte growth factor (HGF) receptor MET is an oncogenic driver in a subpopulation of Non-small Lung Cancer Cells (NSCLC) at the primary tumor stage or in acquired resistance to treatment with tumor-targeting tyrosine kinase inhibitors (TKIs). AREAS COVERED This article summarizes the mechanisms leading to overexpression and activation of MET by amplification and mutations including exon 14 aberrations. Furthermore, the methods to detect and categorize MET as a tumor driver and the selective TKIs for patient treatment are discussed. EXPERT OPINION : Activating mutations and rearrangements of kinases in NSCLC are the target of successful therapeutic intervention. However, MET activation involves a number of complex alterations including gene amplification, prevention of degradation by METex14 exon skipping and a host of gene mutations. A high-level of MET expression is the precondition for tumor responses to TKIs and the confirmation of MET-dependent tumor progression is difficult in primary lesions and in tumors exhibiting resistance to mutated EGFR-directed therapy in absence of standardized and concordant assays of MET amplification.
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Affiliation(s)
- Gerhard Hamilton
- Department of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Barbara Rath
- Department of Pharmacology, Medical University of Vienna, Vienna, Austria
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Ramani NS, Morani AC, Zhang S. MET Gene High Copy Number (Amplification/Polysomy) Identified in Melanoma for Potential Targeted Therapy. Am J Clin Pathol 2022; 157:502-505. [PMID: 34617988 DOI: 10.1093/ajcp/aqab171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/01/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Aberrant expression of the mesenchymal epithelial transition factor (MET) gene has been observed in several malignancies, and drugs targeting the MET gene have been implicated in clinical trials with promising results. Hence, MET is a potentially targetable oncogenic driver. We explored the frequency of MET gene high copy number in melanomas and carcinomas. METHODS The study group included 135 patients. Tissue microarrays were constructed with 19 melanomas and 116 carcinomas diagnosed from 2010 to 2012. We screened MET gene copy number by fluorescence in situ hybridization analysis using probes for MET gene and CEP7 as control. RESULTS We found MET gene amplification in 2 (11%) of 19 melanoma cases, whereas 5 (26%) of 19 melanoma cases showed polysomy. For carcinomas, there was no MET gene amplification identified. However, 8 (7%) of 116 cases showed polysomy. CONCLUSIONS In our study, MET gene amplification was identified in 11% of melanomas and is relatively concordant with few reported studies. However, about 26% of the additional melanoma cases showed MET gene polysomy, which has not been reported as per our knowledge. If these results are validated with further orthogonal studies, more of the melanoma cases could potentially benefit from targeted therapy with MET tyrosine kinase inhibitors.
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Affiliation(s)
- Nisha S Ramani
- Department of Pathology, Upstate Medical University, Syracuse, NY, USA
| | | | - Shengle Zhang
- Department of Pathology, Upstate Medical University, Syracuse, NY, USA
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Met–HER3 crosstalk supports proliferation via MPZL3 in MET-amplified cancer cells. Cell Mol Life Sci 2022; 79:178. [PMID: 35249128 PMCID: PMC8898245 DOI: 10.1007/s00018-022-04149-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 12/11/2022]
Abstract
AbstractReceptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3–tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in vitro and in vivo. Gene expression analysis of HER3-depleted cells identified MPZL3, encoding a single-pass transmembrane protein, as HER3-dependent effector in multiple MET-amplified cancer cell lines. MPZL3 interacts with HER3 and MPZL3 loss phenocopies HER3 loss in MET-amplified cells, while MPZL3 overexpression can partially rescue proliferation upon HER3 depletion. Together, these data support an oncogenic role for a HER3–MPZL3 axis in MET-amplified cancers.
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Coleman N, Harbery A, Heuss S, Vivanco I, Popat S. Targeting un-MET needs in advanced non-small cell lung cancer. Lung Cancer 2021; 164:56-68. [PMID: 35033939 DOI: 10.1016/j.lungcan.2021.12.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 12/27/2021] [Indexed: 12/22/2022]
Abstract
Lung cancer classification has been radically transformed in recent years as genomic profiling has identified multiple novel therapeutic targets including MET exon 14 (METex14) alterations and MET amplification. Utilizing targeted therapies in patients with molecularly-defined NSCLC leads to remarkable objective response rates and improved progression-free survival. However, acquired resistance is inevitable. Several recent phase II trials have confirmed that METex14 NSCLC can be treated effectively with MET kinase inhibitors, such as crizotinib, capmatinib, tepotinib, and savolitinib. However, response rates for many MET TKIs are modest relative to the activity of targeted therapy in other oncogene-driven lung cancers, where ORRs are more consistently greater than 60%. In spite of significant gains in the field of MET inhibition in NSCLC, challenges remain: the landscape of resistance mechanisms to MET TKIs is not yet well characterized, and there may be intrinsic and acquired resistance mechanisms that require further characterization to enable increased MET TKI activity. In this review, we overview MET pathway dysregulation in lung cancer, methods of detection in the clinic, recent clinical trial data, and discuss current mechanisms of TKI resistance, exploring emerging strategies to overcome resistance.
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Affiliation(s)
- Niamh Coleman
- Lung Unit. The Royal Marsden Hospital, 203 Fulham Rd, Chelsea, London SW3 6JJ, UK; Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK; University of Texas MD Anderson Cancer Center, Texas, USA.
| | - Alice Harbery
- Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
| | - Sara Heuss
- Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
| | - Igor Vivanco
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Sanjay Popat
- Lung Unit. The Royal Marsden Hospital, 203 Fulham Rd, Chelsea, London SW3 6JJ, UK; Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
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Mi J, Huang Z, Zhang R, Zeng L, Xu Q, Yang H, Lizaso A, Tong F, Dong X, Yang N, Zhang Y. Molecular characterization and clinical outcomes in EGFR-mutant de novo MET-overexpressed advanced non-small-cell lung cancer. ESMO Open 2021; 7:100347. [PMID: 34953403 PMCID: PMC8717426 DOI: 10.1016/j.esmoop.2021.100347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/19/2021] [Accepted: 11/20/2021] [Indexed: 11/26/2022] Open
Abstract
Background Approximately 2%-8% of non-small-cell lung cancer (NSCLC) harbors concurrent epidermal growth factor receptor (EGFR) sensitizing mutation and mesenchymal–epithelial transition factor (MET) amplification prior to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to investigate the optimal first-line therapeutic options for patients with concurrent EGFR-mutant, MET-overexpressed/amplified advanced NSCLC. Methods A total of 104 treatment-naïve patients with EGFR-mutant de novo MET-overexpressed advanced NSCLC were identified using immunohistochemistry and stratified to four groups according to treatment regimen: EGFR-TKI monotherapy (n = 48), EGFR-TKI combined with either crizotinib (n = 9) or chemotherapy (n = 12), and chemotherapy (n = 35). A subpopulation of 28 patients was also tested with next-generation sequencing (NGS). Objective response rate (ORR) and progression-free survival (PFS) outcomes were analyzed according to treatment strategies and molecular features. Results All the patients (n = 104) achieved ORR of 36.5% and median PFS (mPFS) of 7.0 months. Baseline clinicopathologic characteristics were similar among the four treatment groups. Compared with chemotherapy, EGFR-TKI monotherapy or EGFR-TKI combination therapy achieved significantly higher ORR (P < 0.001) and longer mPFS (P = 0.003). No ORR or PFS difference was observed between EGFR-TKI monotherapy and combination therapy. In the NGS-identified population (n = 28), patients who received EGFR-TKI plus crizotinib (n = 9) achieved similar ORR (88.9% versus 57.9%, P = 0.195) and mPFS (9.0 versus 8.5 months, hazard ratio 1.10, 95% confidence interval 0.43-2.55, P = 0.45) than those who received EGFR-TKI monotherapy (n = 19), regardless of MET copy number status. Grade 3/4 rashes were significantly more among patients who received EGFR-TKI plus crizotinib (P = 0.026). Conclusions Our findings provided clinical evidence that patients with concurrent EGFR sensitizing mutation and de novo MET amplification/overexpression could benefit from first-line EGFR-TKI monotherapy.
Concomitant EGFR sensitizing mutation and MET overexpression/amplification were detected in 2.6% of lung cancer patients. EGFR-TKI monotherapy elicited a higher response rate and longer PFS than chemotherapy. EGFR-TKI with or without crizotinib elicited comparable PFS regardless of MET copy number. EGFR-TKI monotherapy achieved lower number of grade 3/4 adverse events than EGFR-TKI plus crizotinib.
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Affiliation(s)
- J Mi
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Graduate School, University of South China, Hengyang, Hunan, China
| | - Z Huang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Graduate School, University of South China, Hengyang, Hunan, China
| | - R Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - L Zeng
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Q Xu
- Department of Medical Oncology, Qinghai Provincial People's Hospital, Xining, China
| | - H Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - A Lizaso
- Burning Rock Biotech, Guangzhou, China
| | - F Tong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - X Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - N Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Graduate School, University of South China, Hengyang, Hunan, China.
| | - Y Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Graduate School, University of South China, Hengyang, Hunan, China.
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Cai B, Li X, Huang X, Ma T, Qu B, Yu W, Yang W, Zhang P, Chen J, Liu F. Case Report: Sequential Combination Targeted Therapy With Type I and II MET Inhibitors in a Metastatic EGFR-Mutated, MET-Amplified NSCLC Patient With Acquired MET Y1230H Mutation. Front Oncol 2021; 11:738832. [PMID: 34926253 PMCID: PMC8674488 DOI: 10.3389/fonc.2021.738832] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 11/17/2021] [Indexed: 12/27/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for advanced non-small-cell lung cancer (NSCLC) patients. However, most patients will eventually develop resistance. For EGFR-TKI resistance mediated by MET amplification, the combination of EGFR and MET TKIs has shown promising results in early clinical trials. However, acquired resistance to MET inhibitors forms a formidable challenge to this dual blockade approach. Here, we presented an NSCLC patient with EGFR exon 19 deletion (ex19del) who was resistant to first-line erlotinib treatment but responded to chemotherapy. Given the finding of MET overexpression/amplification after disease progression, the patient received gefitinib plus crizotinib with a partial response. Her disease progressed again, and molecular testing revealed a novel MET Y1230H mutation and a PD-L1 TPS score of 75%. She received a salvage regime consisting of gefitinib, cabozantinib, and pembrolizumab with a partial response. Since we now know that EGFR ex19del NSCLC patients generally do not respond to PD-1 blockade therapy, this response is more likely the contribution from gefitinib plus cabozantinib. Therefore, sequential use of type I and II MET inhibitors in EGFR/MET dual blockade may be an effective therapeutic option for EGFR-mutant, MET-amplified NSCLC.
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Affiliation(s)
- Boning Cai
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Xiaomo Li
- Department of Translational Medicine, Genetron Health (Beijing) Technology, Co. Ltd, Beijing, China
| | - Xiang Huang
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Tonghui Ma
- Department of Translational Medicine, Genetron Health (Beijing) Technology, Co. Ltd, Beijing, China
| | - Baolin Qu
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Wei Yu
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Wei Yang
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Pei Zhang
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Jing Chen
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Fang Liu
- Department of Radiation Oncology, The First Medical Center, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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Song Y, Li G, Ju K, Ran W, Zhao H, Liu X, Hou M, He Y, Chen Y, Zang G, Xing X. Mesenchymal-Epithelial Transition Exon 14 Skipping Mutation and Amplification in 5,008 Patients With Lung Cancer. Front Oncol 2021; 11:755031. [PMID: 34660325 PMCID: PMC8515048 DOI: 10.3389/fonc.2021.755031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 09/10/2021] [Indexed: 11/13/2022] Open
Abstract
Background Lung cancer is a major health concern worldwide because of its increasing incidence and mortality. This study aimed to clarify the association between mesenchymal-epithelial transition (MET) genomic alterations and clinical characteristics of lung cancer. Method We collected data from 5,008 patients with lung cancer diagnosed and treated between January 2017 and July 2021 at the Affiliated Hospital of Qingdao University. Genomic alterations in the MET gene, including the exon 14 skipping mutation and amplification, were detected using amplification refractory mutation system-polymerase chain reaction (2,057 cases) and next-generation sequencing (2,951 cases). Clinical characteristics such as age, sex, tumor location, tumor stage, smoking, pleural invasion, and histology were statistically analyzed for MET exon 14 skipping mutation and amplification. The DNA splicing sites causing the MET exon 14 skipping mutation at the mRNA level were also investigated. Results The incidence of the MET exon 14 skipping mutation was 0.90% (41/4,564) in adenocarcinoma, 1.02% (3/294) in squamous cell carcinoma, and 8.33% (1/12) in sarcomatoid carcinoma specimens. It was more frequently observed in patients over 60 years of age than the MET exon 14 skipping mutation wildtype. The MET exon 14 skipping mutation co-occurred with epidermal growth factor receptor (EGFR) L858R, EGFR 19-Del, and BRAF V600E mutations. At the DNA level, single nucleotide mutation and small fragment deletion (1-38 base pairs) upstream and downstream of MET exon 14 led to MET exon 14 skipping mutation at the mRNA level. MET amplification occurred in 0.78% (21/2,676) adenocarcinoma and 1.07% (2/187) squamous cell carcinoma specimens and was significantly associated with advanced tumor stages (III + IV) compared to the MET amplification wildtype. MET amplification primarily co-occurred with the EGFR mutation. Conclusions Our study found that MET genomic alterations were statistically related to age and tumor stage and co-existed with mutations of other oncogenic driver genes, such as EGFR and BRAF. Moreover, various splicing site changes at the DNA level led to the exon 14 skipping mutation at the mRNA level. Further studies are required to clarify the association between MET genomic alterations and prognosis.
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Affiliation(s)
- Yaolin Song
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guangqi Li
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kun Ju
- Department of Emergency, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenwen Ran
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Han Zhao
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xianglan Liu
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Mingyu Hou
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yulu He
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yang Chen
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Guoliang Zang
- Department of Technical, Geneis Beijing Co., Ltd., Beijing, China
| | - Xiaoming Xing
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
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MET Amplification in Non-Small Cell Lung Cancer (NSCLC)-A Consecutive Evaluation Using Next-Generation Sequencing (NGS) in a Real-World Setting. Cancers (Basel) 2021; 13:cancers13195023. [PMID: 34638507 PMCID: PMC8508248 DOI: 10.3390/cancers13195023] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Lung cancer has a high incidence and affects both men and women. Targeted therapy options directed at certain mutant proteins, and which avoid systemic chemotherapy are already available and emerging. The gene mesenchymal epithelial transition (MET), encoding a receptor tyrosine kinase protein, is amplified in a subpopulation of lung cancer patients. The aim of our consecutive study was to assess whether next-generation sequencing (NGS) is a reliable method for the detection of MET gene copy number. Our study confirmed that NGS is able to detect cases harboring a high-level MET gene amplification but is unreliable and fails to detect the various levels of MET gene amplification. Therefore, NGS cannot replace the gold standard method of fluorescence in situ hybridization for the detection of MET gene copy number. Abstract In non-small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high-level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the MET GCN detects high-level MET amplified cases harboring a MET GCN > 10 but fails to detect the various facets of MET gene amplification in the context of a therapy-induced resistance mechanism.
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Liu M. Combination treatment with trastuzumab and crizotinib in metastatic gastric cancer harboring Her-2 amplification and c-MET amplification: A case report. Medicine (Baltimore) 2021; 100:e27017. [PMID: 34516491 PMCID: PMC8428754 DOI: 10.1097/md.0000000000027017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/05/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Metastatic gastric cancer patients with poor eastern cooperative oncology group performance status (PS) (≥3) were lack of effective anti-tumor strategies. They always lived with poor PS, severe and multiple symptoms, and usually resulted in extremely limited survival time. Herein, we reported a patient diagnosed with gastric cancer metastasized to multiple bones, along with lymphangitis carcinomatosa in lungs, harboring Her-2 and c-MET amplification with poor PS, positively responded to combinational therapy with trastuzumab and crizotinib. PATIENT CONCERNS The patient complained of persistent cough and fatigue for 2 months, otherwise, she denied smoking, alcohol history, or any other medical or family history. DIAGNOSIS With the biopsy results from gastroscopy, as well as computer tomography for chest and abdomen, the patient was diagnosed as gastric adenocarcinoma, with metastasis on lungs, left adrenal gland, retroperitoneal lymph nodes, and multiple bones. INTERVENTIONS Because of the poor PS (PS = 3), as well as Her-2 and c-MET amplification, the patient received combination treatment with trastuzumab and crizotinib as salvage strategy. OUTCOMES After 2 months' exposure of trastuzumab and crizotinib, symptoms including persistent cough, and chest distress were alleviated significantly. Simultaneously, chest computer tomography showed significant dissipation of lymphangitis carcinomatosa, as well as apparent reduction of pleural effusion. No adverse reactions including nausea, vomiting, diarrhea, or hypertension was observed during the following 2 months. LESSONS The present case suggested that combinational therapy with trastuzumab and crizotinib might be effective in metastatic gastric cancer patients harboring Her-2 and c-MET amplification, even with a poor PS. It was also implied that gene sequencing might be valuable, especially in patients with limited treatment strategies.
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Lu Q, Ni Y, Wang W, Wang L, Jiang T, Shang L. Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET-GBR2-STAT3 Complex Formation. Front Cell Dev Biol 2021; 9:641403. [PMID: 34490234 PMCID: PMC8416685 DOI: 10.3389/fcell.2021.641403] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 07/20/2021] [Indexed: 01/05/2023] Open
Abstract
Dynamin 3 (DNM3) has gained increased attention ever since its potential as a tumor suppressor was reported. However, its action in lung cancer (LC) is undefined. In this study, the role of DNM3 in LC development was investigated. DNM3 expression was found to be downregulated in tumors of patients with LC, especially those with metastasis. The DNM3 downregulation enhanced the proliferative and metastatic ability of LC cells, whereas its upregulation had the opposite effects. In vivo xenograft experiments confirmed that lung tumors with lower DNM3 expression had higher growth and metastatic abilities. Mechanistic studies revealed that DNM3 interacts with growth factor receptor-bound protein 2 (GBR2), thereby interrupting tyrosine-protein kinase Met (c-MET)-GBR2-signal transducer and activator of transcription 3 (STAT3) complex formation, which suppressed STAT3 activation. Therefore, the absence of DNM3 frees GBR2 to activate STAT3, which regulates the expression of genes related to LC proliferation and metastasis (e.g., cyclin D1 and Snail family transcriptional repressor 1). Additionally, the c-MET inhibitor crizotinib effectively suppressed LC cell proliferation and migration in vitro and in vivo, even with DNM3 depleted. Therefore, our study has demonstrated the antitumor effect of DNM3 in LC and suggests that the inhibition of c-MET might be a promising strategy for treating those LC patients with low DNM3 expression.
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Affiliation(s)
- Qiang Lu
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, China
| | - Yunfeng Ni
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, China
| | - Wuping Wang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, China
| | - Lei Wang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, China
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, China
| | - Lei Shang
- The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Department of Health Statistics, School of Public Health, The Air Force Military Medical University, Xi’an, China
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Lakshmanan S, Govindaraj D, Mahalakshmi K, Thirumurugan K, Ramalakshmi N, Antony SA. Synthesis, characterization, and anti-cancer activity of chalcone derivatives as-potent anaplastic lymphoma kinase inhibitors. Struct Chem 2021. [DOI: 10.1007/s11224-020-01707-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Fu J, Su X, Li Z, Deng L, Liu X, Feng X, Peng J. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 2021; 40:4625-4651. [PMID: 34145400 DOI: 10.1038/s41388-021-01863-w] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal-epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.
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Affiliation(s)
- Jianjiang Fu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xiaorui Su
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Zhihua Li
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
- Department of Fetal Medicine and Prenatal Diagnosis, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ling Deng
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiawei Liu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xuancheng Feng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
| | - Juan Peng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
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Moreno V, Greil R, Yachnin J, Majem M, Wermke M, Arkenau HT, Basque JR, Nidamarthy PK, Kapoor S, Cui X, Giovannini M. Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors. Clin Ther 2021; 43:1092-1111. [PMID: 34053700 DOI: 10.1016/j.clinthera.2021.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/06/2021] [Accepted: 04/11/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors. METHODS This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety. FINDINGS Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median Tmax for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUCtau and Cmax) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%). IMPLICATIONS Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.
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Affiliation(s)
- Victor Moreno
- START Madrid-FJD, Hospital Fundación Jímenez Díaz, Madrid, Spain.
| | - Richard Greil
- IIIrd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute, Salzburg, Austria
| | - Jeffrey Yachnin
- Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Margarita Majem
- Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Martin Wermke
- Medical Clinic I, University Hospital Carl Gustav Carus, NCT/UCC Early Clinical Trial Unit, Dresden, Germany
| | - Hendrik-Tobias Arkenau
- Medical Oncology, Sarah Cannon Research Institute UK, London, United Kingdom; Cancer Institute, University College London, London, United Kingdom
| | | | | | - Shruti Kapoor
- Novartis Healthcare Private Limited, Hyderabad, India
| | - Xiaoming Cui
- Novartis Institutes for BioMedical Research, East Hanover, New Jersey
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Tartarone A, Lapadula V, Di Micco C, Rossi G, Ottanelli C, Marini A, Giorgione R, Ferrari K, Catalano M, Voltolini L, Mini E, Roviello G. Beyond Conventional: The New Horizon of Targeted Therapy for the Treatment of Advanced Non Small Cell Lung Cancer. Front Oncol 2021; 11:632256. [PMID: 34094913 PMCID: PMC8176852 DOI: 10.3389/fonc.2021.632256] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 04/20/2021] [Indexed: 12/25/2022] Open
Abstract
In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.
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Affiliation(s)
- Alfredo Tartarone
- Department of Onco-Hematology, Division of Medical Oncology IRCCS-CROB Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Vittoria Lapadula
- Department of Onco-Hematology, Division of Medical Oncology IRCCS-CROB Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Concetta Di Micco
- Division of Medical Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Gemma Rossi
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Carlotta Ottanelli
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Andrea Marini
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Roberta Giorgione
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Katia Ferrari
- Respiratory Medicine, Careggi University Hospital, Florence, Italy
| | - Martina Catalano
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Luca Voltolini
- Thoracic Surgery Unit, Careggi University Hospital, Florence, Italy
| | - Enrico Mini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
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Yang J, Zhou P, Yu M, Zhang Y. Case Report: High-Level MET Amplification as a Resistance Mechanism of ROS1-Tyrosine Kinase Inhibitors in ROS1-Rearranged Non-Small Cell Lung Cancer. Front Oncol 2021; 11:645224. [PMID: 34055614 PMCID: PMC8155543 DOI: 10.3389/fonc.2021.645224] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/26/2021] [Indexed: 02/05/2023] Open
Abstract
Background Although C-ros oncogene 1 (ROS1) targeted therapies have demonstrated remarkable efficacy in ROS1-rearranged non-small cell lung cancer (NSCLC), patients inevitably develop resistance to ROS1-tyrosine kinase inhibitors (TKIs). Commonly acquired resistance mechanisms include a second mutation of the ROS1 kinase domain and activation of bypass signaling pathways. However, MMNG HOS Transforming gene (MET) amplification has not been reported as a novel mechanism of ROS1-TKIs resistance. Case Presentation We report a case of a 62-year-old man diagnosed with ROS1-rearranged metastatic lung adenocarcinoma, who received first-line treatment with crizotinib for 19 months. During the course of disease, the primary lung tumor was under control while the brain metastasis progressed despite the treatment with lorlatinib. The biopsy and genetic tests of the metastatic brain tumor showed a high level of MET amplification (32 copies). However, fluorescence in situ hybridization of the primary cancer showed no MET amplification, suggesting that MET amplification may be associated with an acquired resistance to ROS1-TKIs. Summary This case suggested that MET amplification could be explored as a potential mechanism for developing ROS1-TKIs resistance. Combination treatment with highly potent and selective MET-TKIs warrants further investigations.
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Affiliation(s)
- Jiangping Yang
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Ping Zhou
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Min Yu
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
| | - Yan Zhang
- Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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An HJ, An E, Rabizadeh S, Liao WL, Burrows J, Hembrough T, Kang JH, Park CK, Kim TJ. Quantitative Multiplexed Proteomics Could Assist Therapeutic Decision Making in Non-Small Cell Lung Cancer Patients with Ambiguous ALK Test Results. Cancers (Basel) 2021; 13:cancers13102337. [PMID: 34066104 PMCID: PMC8150487 DOI: 10.3390/cancers13102337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 11/16/2022] Open
Abstract
Therapeutic guidance in non-small cell lung cancer (NSCLC) tumors that are positive for anaplastic lymphoma kinase (ALK) fluorescent in situ hybridization (FISH), but negative for ALK immunohistochemistry, is still challenging. Parallel routine screening of 4588 NSCLC cases identified 22 discordant cases. We rechecked these samples using ALK antibodies and selected reaction monitoring (SRM) quantitative multiplexed proteomics screening multiple protein targets, including ALK and MET for the ALK tyrosine kinase inhibitor (TKI), and FR-alpha, hENT1, RRM1, TUBB3, ERCC1, and XRCC1 for chemotherapy. The presence of ALK (31.8%), MET (36.4%), FR-alpha (72.7%), hENT1 (18.2%), RRM1 (31.8%), TUBB3 (72.9%), ERCC1 (4.5%), and a low level of XRCC1 (54.4%) correlated with clinical outcomes. SRM was more sensitive than the ALK D5F3 assay. Among the eight cases receiving ALK TKI, four cases with ALK or MET detected by SRM had complete or partial responses, whereas four cases without ALK or MET showed progression. Twenty-seven treatment outcomes from 20 cases were assessed and cases expressing more than half of the specific predictive proteins were sensitive to matching therapeutic agents and showed longer progression-free survival than the other cases (p < 0.001). SRM showed a potential role in therapeutic decision making in NSCLC patients with ambiguous ALK test results.
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Affiliation(s)
- Ho Jung An
- Department of Medical Oncology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Eunkyung An
- NantOmics, Culver City, CA 90232, USA; (E.A.); (S.R.); (W.-L.L.)
| | | | - Wei-Li Liao
- NantOmics, Culver City, CA 90232, USA; (E.A.); (S.R.); (W.-L.L.)
| | - Jon Burrows
- OncoPlex Diagnostics, Rockville, MD 20850, USA; (J.B.); (T.H.)
| | - Todd Hembrough
- OncoPlex Diagnostics, Rockville, MD 20850, USA; (J.B.); (T.H.)
| | - Jin Hyung Kang
- Department of Medical Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Chan Kwon Park
- Division of Pulmonology, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Tae-Jung Kim
- Department of Hospital Pathology, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
- Correspondence: ; Tel.: 82-2-3779-2157
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Haranguş A, Berindan-Neagoe I, Toma L, Şimon I, Pop O, Şimon M. EBUS in optimizing non-small cell lung cancer diagnosis and treatment. Med Pharm Rep 2021; 94:176-184. [PMID: 34013188 PMCID: PMC8118210 DOI: 10.15386/mpr-1725] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/14/2020] [Accepted: 07/31/2020] [Indexed: 12/12/2022] Open
Abstract
Background Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a commonly used minimally invasive method for the diagnosis and staging of lung cancer. In order to improve its diagnostic accuracy, rapid on-site cytologic evaluation (ROSE) is being utilized in some institutions. ROSE, performed by a cytopathologist in the examination room, allows the assessment of the adequacy of the collected samples, identifies malignant cells and sometimes establishes diagnosis on the spot, thus improving diagnostic sensitivity. As non-small cell lung carcinomas (NSCLC) require not only pathological subtyping, but also molecular characterization, obtaining the adequate amount of tissue is crucial. Only a limited number of studies have analyzed the suitability of EBUS-TBNA samples for assessment of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and programmed death-ligand 1 (PD-L1) status. Aim We intended to examine the diagnostic yield of ROSE in NSCLC and the results and feasibility of molecular analysis performed on EBUS-TBNA small samples. Methods 100 patients with lung tumors and hilar and/or mediastinal lymphadenopathy on CT or PET/CT scans were retrospectively identified over a 3-year period, from a prospectively maintained EBUS-TBNA database. All examinations were accompanied by on-site cytological exam - ROSE, histopathological exam (HPE) and, in the case of NSCLC, molecular testing. After the sampling of the lymph nodes, specimens were Diff-Quik stained and a rapid preliminary diagnosis was established. Immunohistochemistry and mutational testing were performed using cell blocks. Results Adenocarcinoma was the most frequent diagnosis in both ROSE (34%) and histopathology (53%). Overall sensitivity and positive predictive value of ROSE in NSCLC, considering HPE the gold standard, were 92.18% and 93.65%, respectively, with a specificity and negative predictive value of 75% and 70.58%, respectively. All samples that were tested for EGFR mutation and ALK rearrangement were adequate for analysis. The adequacy ratio for PD-L1 was 91.66%; 37.5% of patients showed a high PD-L1 expression level, with a tumor proportion score TPS ≥50%. Conclusion EBUS-TBNA is a valuable method for lung cancer diagnosis. ROSE proved to have a moderate prediction of the final diagnosis in NSCLC. Molecular analysis of EGFR, ALK and PD-L1 can be successfully accomplished on EBUS-TBNA small tissue samples.
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Affiliation(s)
- Antonia Haranguş
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Leon Daniello Pulmonology Hospital, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,MEDFUTURE-Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, "Prof. Dr. Ion Chiricuta" Oncology Institute, Cluj-Napoca, Romania
| | | | - Ioan Şimon
- Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
| | | | - Mărioara Şimon
- Leon Daniello Pulmonology Hospital, Cluj-Napoca, Romania
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Yang L, Gu J, Niu X. Complex renal cysts combined with hemorrhage during crizotinib treatment for ALK-rearranged lung adenocarcinoma. Cancer Treat Res Commun 2021; 27:100373. [PMID: 33865115 DOI: 10.1016/j.ctarc.2021.100373] [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: 01/25/2021] [Revised: 03/28/2021] [Accepted: 04/07/2021] [Indexed: 06/12/2023]
Abstract
The oral small-molecule tyrosine kinase inhibitor (TKI), crizotinib has been approved as a first-generation anaplastic lymphoma kinase (ALK) inhibitor in treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). Recently, development of complex renal cysts has been reported with crizotinib usage, highlighting the importance of accurate differentiation between complex renal cysts and new metastasis in NSCLC. Here we describe a case study with confirmed EGFR wild-type and ALK-rearranged lung adenocarcinoma who developed complex renal cysts combined with hemorrhage during crizotinib treatment, with no abnormal clinical symptoms or kidney functions observed. Interestingly, without crizotinib treatment termination or reduction, the complex hemorrhagic renal cysts regressed with self-limiting and healing. The combined usage of ultrasound, CT and MRI techniques in the presented case allowed proper monitoring of the internal changes within complex renal cysts. The patient provided written informed consent authorizing publication of clinical case. Thus, better understanding of the imaging features of crizotinib-related renal cysts combined with hemorrhage would avoid misdiagnoses as a new metastatic renal mass or the aggravation of the primary disease, therefore avoiding further invasive investigation.
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Affiliation(s)
- Ling Yang
- Department of Ultrasonography, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui District, West Huaihai Road No. 241, Shanghai, China
| | - Jianing Gu
- Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Minhang District, Heqing Road No. 801, Shanghai, China
| | - Xiaomin Niu
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui District, West Huaihai Road No. 241, Shanghai, China.
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