MGST1 facilitates novel KRASG12D inhibitor resistance in KRASG12D-mutated pancreatic ductal adenocarcinoma by inhibiting ferroptosis

作者：Chungui Xu, Weihao Lin, Qi Zhang, Yarui Ma, Xue Wang, Xue Wang, Ai Guo, Zhendiao Zhou, Zhendiao Zhou, Weiwei Song, Ziyi Zhao, Yuchen Jiao, Xiaobing Wang, Xiaobing Wang, Chunxia Du · 发表于：Molecular Medicine · 年份：2024 · DOI：10.1186/s10020-024-00972-y · 被引用次数：10 · 研究领域：Pancreatic and Hepatic Oncology Research、Ferroptosis and cancer prognosis、RNA modifications and cancer

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a low 5-year survival rate. Treatment options for PDAC patients are limited. Recent studies have shown promising results with MRTX1133, a KRAS G12D inhibitor that demonstrated potent antitumor activity in various types of tumors with KRAS G12D mutation. Resistance to KRAS inhibitors is frequently occurred and one of the main reasons for treatment failure. Understanding resistance mechanisms to novel KRAS inhibitors is crucial to ensure sustained and durable remissions. Methods Two KRAS G12D inhibitor MRTX1133-resistant PDAC cell lines were established in vitro. The resistance mechanisms to KRAS G12D inhibitor MRTX1133 against PDAC in vitro and in vivo were characterized by RNA sequencing, reverse transcript polymerase chain reaction, cytotoxicity test, plasmid transfection, lentivirus transfection, lipid peroxidation detection, malondialdehyde levels detection, glutathione levels detection, western blot, immunofluorescence, nude mice tumorigenesis experiment and immunohistochemistry. Results The bioinformatics analysis and transcriptome sequencing showed that ferroptosis was involved in the resistant effect of the KRAS G12D inhibitor treatment, and MGST1 was the key molecule against MRTX1133-induced ferroptosis. Increased expression of MGST1 weakened the cytotoxicity of MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis in KRAS G12D inhibitor-resistant PDAC cells. Knockdown o...