c-MET inhibition is synthetic lethal with ARID1A loss via targeting GPX4 and promoting ferroptosis

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 triple genetic interactions between ARID1A, c-MET, and GPX4 in CRC cells, where GPX4, a key regulator of ferroptosis, is a common transcription target of ARID1A and c-MET signaling. ARID1A inactivation significantly downregulated both c-MET and GPX4 levels, and the c-MET inhibitor further diminished GPX4 levels in ARID1A-deficient CRC cells, leading to increased lipid peroxidation and glutathione depletion, ultimately inducing ferroptosis. This study reveals a novel synthetic lethal relationship between ARID1A and c-MET signaling in promoting ferroptosis and proposes c-MET inhibitors as a potential therapeutic strategy for ARID1A-deficient CRC. Overall design: RNA-seq