ARID1A loss enhances sensitivity to c-MET inhibition by dual targeting of GPX4 and iron homeostasis, inducing ferroptosis.

ABSTRACT: ARID1A, a subunit of the SWI/SNF chromatin-remodeling complex, functions as a tumor suppressor in various cancer types. Owing to its high frequency of inactivating mutations, ARID1A has emerged as a promising target for the development of anticancer drugs. In this study, we report that ARID1A-deficient colorectal cancer (CRC) cells induce synthetic lethality when treated with inhibitors of c-MET receptor tyrosine kinase. c-MET specific inhibitor PHA-665752 as well as two other FDA-approved drugs, crizotinib and cabozantinib, selectively inhibited the growth of ARID1A-deficient CRC cells in vitro and in xenograft tumor models. Mechanistically, we identified a tripartite functional association among ARID1A, c-MET, and NRF2, where ARID1A and c-MET pathways converge on the NRF2 transcription f

SUBMITTER: Zhang X 

PROVIDER: S-EPMC12572266 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature