ARID1A loss enhances sensitivity to c-MET inhibition by dual targeting of GPX4 and iron homeostasis, inducing 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 a tripartite functional association among ARID1A, c-MET, and NRF2, where ARID1A and c-MET pathways converge on the NRF2 transcription factor, which regulates the transcription of GPX4, a key regulator of ferroptosis. ARID1A inactivation reduces c-MET expression, decreasing NRF2 nuclear localization and its binding to the GPX4 promoter, resulting in reduced GPX4 transcription. This creates a cellular dependency on the residual c-MET for minimal GPX4 expression to survive the ferroptotic cell death. Additionally, we demonstrate that ARID1A loss leads to increased intracellular labile iron accumulation by downregulating the iron-exporting protein SLC40A1, thereby increasing cellular susceptibility to ferroptosis. Inhibition of c-MET in ARID1A-deficient CRC cells diminishes GPX4 expression, resulting in elevated 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.