Department of Medicine.
Department of Cellular and Molecular Pharmacology, and.
J Clin Invest. 2022 Feb 15;132(4). doi: 10.1172/JCI156891.
KRAS G12C inhibitors such as sotorasib and adagrasib are often effective in KRAS G12C-driven non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits long-term patient survival. In this issue of the JCI, Tsai et al. present a comprehensive genetic analysis of multiple tumors with acquired sotorasib resistance obtained through an autopsy of a patient with KRAS G12C-mutant NSCLC. This analysis of pre- and posttreatment tumors uncovered cancer cell-intrinsic and -extrinsic features of resistance, including reactivation of KRAS-mediated signaling, reprogramming of metabolism, epithelial-mesenchymal transition, and tumor microenvironment changes. This elegant study demonstrates the multifaceted nature of KRAS G12C inhibitor clinical resistance and potential avenues to overcome resistance.
KRAS G12C 抑制剂，如 sotorasib 和 adagrasib，在 KRAS G12C 驱动的非小细胞肺癌（NSCLC）患者中通常有效。然而，获得性耐药限制了患者的长期生存。在本期 JCI 中，Tsai 等人对一名 KRAS G12C 突变 NSCLC 患者尸检获得的多个获得性 sotorasib 耐药肿瘤进行了全面的遗传分析。对治疗前后肿瘤的分析揭示了耐药的肿瘤细胞内在和外在特征，包括 KRAS 介导的信号重新激活、代谢重编程、上皮-间充质转化和肿瘤微环境变化。这项精巧的研究表明了 KRAS G12C 抑制剂临床耐药的多面性和克服耐药的潜在途径。
