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Cell Death and Differentiation

Cell Death and Differentiation

IF: 15.4
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ARID1A loss enhances sensitivity to c-MET inhibition by dual targeting of GPX4 and iron homeostasis, inducing ferroptosis

Published:14 May 2025 DOI: 10.1038/s41418-025-01510-x
Xu Zhang, Zihuan Wang, Yilin He, Kejin Wang, Cheng Xiang, Yongfeng Liu, Yijiang Song, Aimin Li, Zhen Wang, Yingnan Yu, Wenxuan Peng, Side Liu, Joong Sup Shim, Changjie Wu

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 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.

Substances (14)

Materials
Procduct Name CAS Molecular Formula Supplier Price
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 284 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 284 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 284 suppliers $16.00-$2691.10
2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone 571203-78-6 C30H31ClN4O4 284 suppliers $16.00-$2691.10
RSL3 1219810-16-8 C23H21ClN2O5 218 suppliers $13.00-$2492.00
RSL3 1219810-16-8 C23H21ClN2O5 218 suppliers $13.00-$2492.00
RSL3 1219810-16-8 C23H21ClN2O5 218 suppliers $13.00-$2492.00
RSL3 1219810-16-8 C23H21ClN2O5 218 suppliers $13.00-$2492.00
(2R)-1-[[5-[(Z)-[5-[[(2,6-DICHLOROPHENYL)METHYL]SULFONYL]-1,2-DIHYDRO-2-OXO-3H-INDOL-3-YLIDENE]METHYL]-2,4-DIMETHYL-1H-PYRROL-3-YL]CARBONYL]-2-(1-PYRROLIDINYLMETHYL)PYRROLIDINE 477575-56-7 C32H34Cl2N4O4S 181 suppliers $30.00-$3411.00
(2R)-1-[[5-[(Z)-[5-[[(2,6-DICHLOROPHENYL)METHYL]SULFONYL]-1,2-DIHYDRO-2-OXO-3H-INDOL-3-YLIDENE]METHYL]-2,4-DIMETHYL-1H-PYRROL-3-YL]CARBONYL]-2-(1-PYRROLIDINYLMETHYL)PYRROLIDINE 477575-56-7 C32H34Cl2N4O4S 181 suppliers $30.00-$3411.00

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