한빛사논문
- 조회277
Eun Ji Lee 1, Seung Yeon Oh 1, You Won Lee 2, Ju Young Kim 1, Min-Je Kim 1, Tae Ho Kim 1, Jii Bum Lee 3, Min Hee Hong 4, Sun Min Lim 1, Anke Baum 5, Lydia Woelflingseder 5, Harald Engelhardt 5, Mark Petronczki 5, Flavio Solca 5, Mi Ran Yun 6*, Byoung Chul Cho 1*
1Yonsei University College of Medicine, Seoul, Korea (South), Republic of.
2Yonsei University College of Medicine, Korea (South), Republic of.
3Yonsei Cancer Center, Seoul City, Korea (South), Republic of.
4Yonsei Cancer Center, Seoul, Korea (South), Republic of.
5Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
6Severance Biomedical Science Institute, Seoul, Korea (South), Republic of.
*These authors contributed equally as co-corresponding authors
Corresponding Author: Mi Ran Yun , Byoung Chul Cho
Abstract
Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) 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 post-progression 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 (BBB).
Conclusions: Our findings highlight the potential of BI-4732, a selective EGFR-TKI with high BBB penetration, targeting a broad range of EGFR mutations, including C797S, warranting clinical development.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-02-14)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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