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Preclinical Study of a Biparatopic METxMET Antibody-Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC

Authors
 Seung Yeon Oh  ;  You Won Lee  ;  Eun Ji Lee  ;  Jae Hwan Kim  ;  YoungJoon Park  ;  Seong Gu Heo  ;  Mi Ra Yu  ;  Min Hee Hong  ;  John DaSilva  ;  Christopher Daly  ;  Byoung Chul Cho  ;  Sun Min Lim  ;  Mi Ran Yun 
Citation
 CLINICAL CANCER RESEARCH, Vol.29(1) : 221-232, 2023-01 
Journal Title
CLINICAL CANCER RESEARCH
ISSN
 1078-0432 
Issue Date
2023-01
MeSH
Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm / genetics ; ErbB Receptors ; Humans ; Immunoconjugates* / therapeutic use ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Mutation ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use ; Proto-Oncogene Proteins c-met
Abstract
Purpose: MET amplification is a frequent mechanism of resistance to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC), and combined treatment with EGFR TKIs and MET TKIs has been explored as a strategy to overcome resistance. However, durable response is invariably limited by the emergence of acquired resistance. Here, we investigated the preclinical activity of REGN5093-M114, a novel antibody-drug conjugate targeting MET in MET-driven patient-derived models.

Experimental Design: Patient-derived organoids, patient-derived cells, or ATCC cell lines were used to investigate the in vitro/in vivo activity of REGN5093-M114.

Results: REGN5093-M114 exhibited significant antitumor efficacy compared with METTKI or unconjugated METxMET biparatopic antibody (REGN5093). Regardless of MET gene copy number, MET-overexpressed TKI-naive EGFR-mutant NSCLC cells responded to REGN5093-M114 treatment. Cell surface MET expression had the most predictive power in determining the efficacy of REGN5093-M114. REGN5093-M114 potently reduced tumor growth of EGFR-mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior osimertinib and savolitinib treatment.

Conclusions: Altogether, REGN5093-M114 is a promising candidate to overcome the challenges facing functional MET pathway blockade.,
Full Text
https://aacrjournals.org/clincancerres/article/29/1/221/711969
DOI
10.1158/1078-0432.CCR-22-2180
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jae Hwan(김재환)
Park, YoungJoon(박영준)
Yu, Mi Ra(유미라)
Yun, Mi Ran(윤미란)
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Heo, Seong Gu(허성구)
Hong, Min Hee(홍민희) ORCID logo https://orcid.org/0000-0003-3490-2195
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/195372
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