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

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

  • Cell Death Differ. 2025 May 14. doi: 10.1038/s41418-025-01510-x.
Xu Zhang # 1,  Zihuan Wang # 1,  Yilin He # 1,  Kejin Wang 1,  Cheng Xiang 1,  Yongfeng Liu 2,  Yijiang Song 3,  Aimin Li 1,  Zhen Wang 1,  Yingnan Yu 1,  Wenxuan Peng 1,  Side Liu 4,  Joong Sup Shim 5,  Changjie Wu 6
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Radiation Oncology, Henan Provincial Key Laboratory of Radiation Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3 Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. sideliu@smu.edu.cn.
  • 5 Cancer Centre, Faculty of Health Sciences, MOE Frontiers Science Centre for Precision Oncology, University of Macau, Taipa, Macau SAR, China. jsshim@um.edu.mo.
  • 6 Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China. backkom8788@smu.edu.cn.
  • # Contributed equally.
PMID: 40369167 DOI: 10.1038/s41418-025-01510-x
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.

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