BDTX-189, a novel tyrosine kinase inhibitor, inhibits cell activity via ERK and AKT pathways in the EGFR C797S triple mutant cells

Rui Wang; Wenrui Cui; Lanxin Li; Xiangkai Wei; Chunhong Chu; Guoliang Zhang; Chenxue Liu; Huixia Xu; Chenyang Liu; Ke Wang; Yanming Li; Lei An

doi:10.1016/j.cbi.2024.111033

BDTX-189, a novel tyrosine kinase inhibitor, inhibits cell activity via ERK and AKT pathways in the EGFR C797S triple mutant cells

Chem Biol Interact. 2024 May 6:395:111033. doi: 10.1016/j.cbi.2024.111033. Online ahead of print.

Authors

Rui Wang¹, Wenrui Cui¹, Lanxin Li¹, Xiangkai Wei¹, Chunhong Chu², Guoliang Zhang², Chenxue Liu¹, Huixia Xu¹, Chenyang Liu¹, Ke Wang², Yanming Li¹, Lei An³

Affiliations

¹ Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, 475000, China.
² Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, 475000, China; Institutes of Traditional Chinese Medicine, School of Pharmacy, Henan University, Kaifeng, 475000, Henan, China.
³ Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, 475000, China; Institutes of Traditional Chinese Medicine, School of Pharmacy, Henan University, Kaifeng, 475000, Henan, China. Electronic address: anlei@henu.edu.cn.

PMID: 38710274
DOI: 10.1016/j.cbi.2024.111033

Abstract

The tertiary mutation C797S in the structural domain of the EGFR kinase is a common cause of resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs). In this study, we used a potent, selective and irreversible inhibitor, BDTX-189, to target EGFR C797S triple mutant cells for cell activity. The study constructed the H1975-C797S (EGFR L858R/T790 M/C797S) cell line using the CRISPR/Cas9 method and investigated its potential as a fourth-generation tyrosine kinase inhibitor via chemosensitivity approach. The results demonstrated its ability to induce cytotoxic effects, and inhibit EGFR L858R/T790 M/C797S cell growth and proliferation in a dose-dependent manner. Meanwhile, BDTX-189 reduces the protein phosphorylation levels of EGFR, ERK, and AKT, promoting apoptosis. Furthermore, BDTX-189 not only inhibits common EGFR triple mutations but also effectively inhibits EGFR L858R mutation and EGFR L858R/T790 M mutation. These findings support the cytotoxic effect of BDTX-189 and its inhibitory effect on cell division and proliferation with the EGFR C797S triple mutation.

Keywords: BDTX-189; C797S; Cytotoxicology; Mutant; Proliferation.