Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors
Kai Wang,
Xin Zhang,
Yufei Fan,
Liang Zhou,
Yajun Duan,
Su Li,
Zhongkan Sun,
Chunqian Zhang,
Haoyu Yang,
Wenxiu Yuan,
Linyuan Peng,
Xiaoyu Ma,
Siliang Xiang,
Tianzhi Wang,
Mei Yang,
Zhenyuan Zhang,
Jiaxuan Wang,
Zhongyuan Wang,
Minxian Qian
Affiliations
Kai Wang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Xin Zhang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Yufei Fan
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Liang Zhou
MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
Yajun Duan
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Su Li
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Zhongkan Sun
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Chunqian Zhang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Haoyu Yang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Wenxiu Yuan
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Linyuan Peng
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Xiaoyu Ma
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Siliang Xiang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Tianzhi Wang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Mei Yang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Zhenyuan Zhang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Jiaxuan Wang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China
Zhongyuan Wang
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China; Corresponding author.
Minxian Qian
State Key Laboratory of Natural Medicines, Department of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China; Corresponding author.
The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.
