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Discovery of a Novel Potent EGFR Inhibitor Against EGFR Activating Mutations and On-Target Resistance in NSCLC

Authors
 Eun Ji Lee  ;  Seung Yeon Oh  ;  You Won Lee  ;  Ju Young Kim  ;  Min-Je Kim  ;  Tae Ho Kim  ;  Jii Bum Lee  ;  Min Hee Hong  ;  Sun Min Lim  ;  Anke Baum  ;  Lydia Woelflingseder  ;  Harald Engelhardt  ;  Mark Petronczki  ;  Flavio Solca  ;  Mi Ran Yun  ;  Byoung Chul Cho 
Citation
 CLINICAL CANCER RESEARCH, Vol.30(8) : 1582-1594, 2024-04 
Journal Title
CLINICAL CANCER RESEARCH
ISSN
 1078-0432 
Issue Date
2024-04
MeSH
Acrylamides* ; Aniline Compounds ; Animals ; Carcinoma, Non-Small-Cell Lung* / drug therapy ; Carcinoma, Non-Small-Cell Lung* / genetics ; Carcinoma, Non-Small-Cell Lung* / pathology ; Drug Resistance, Neoplasm / genetics ; ErbB Receptors / genetics ; Humans ; Indoles* ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Mice ; Mutation ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use ; Pyrimidines*
Abstract
Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) serve as the standard first-line therapy for EGFR-mutated non-small cell lung cancer (NSCLC). Despite the sustained clinical benefits achieved through optimal EGFR-TKI treatments, including the third-generation EGFR-TKI osimertinib, resistance inevitably develops. Currently, there are no targeted therapeutic options available postprogression on osimertinib. Here, we assessed the preclinical efficacy of BI-4732, a novel fourth-generation EGFR-TKI, using patient-derived preclinical models reflecting various clinical scenarios. Experimental Design: The antitumor activity of BI-4732 was evaluated using Ba/F3 cells and patient-derived cell/organoid/xenograft models with diverse EGFR mutations. Intracranial antitumor activity of BI-4732 was evaluated in a brain-metastasis mouse model. Results: We demonstrated the remarkable antitumor efficacy of BI-4732 as a single agent in various patient-derived models with EGFR_C797S-mediated osimertinib resistance. Moreover, BI-4732 exhibited activity comparable to osimertinib in inhibiting EGFR-activating (E19del and L858R) and T790M mutations. In a combination treatment strategy with osimertinib, BI-4732 exhibited a synergistic effect at significantly lower concentrations than those used in monotherapy. Importantly, BI-4732 displayed potent antitumor activity in an intracranial model, with low efflux at the blood–brain barrier. Conclusions: Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high blood–brain barrier penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.
Full Text
https://aacrjournals.org/clincancerres/article/30/8/1582/742134
DOI
38330145
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jii Bum(이기쁨) ORCID logo https://orcid.org/0000-0001-5608-3157
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Hong, Min Hee(홍민희) ORCID logo https://orcid.org/0000-0003-3490-2195
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/200580
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