Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.
Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.
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DOI：
10.1172/jci156891
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发表时间：
2022-02-15
期刊：
影响因子：
--
通讯作者：
Bivona TG
中科院分区：
文献类型：
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作者：
Manabe T;Bivona TG
KRAS G12C抑制剂，如sotorasib和adagrasib，通常对KRAS G12C驱动的非小细胞肺癌(NSCLC)患者有效。然而，获得性耐药性限制了患者的长期生存。在这一期的JCI中，蔡等人。通过对一例KRAS G12C突变的非小细胞肺癌患者尸检获得的获得性Sotorasib耐药的多发性肿瘤进行了全面的遗传分析。这项对治疗前后肿瘤的分析揭示了癌细胞的内在和外在耐药特征，包括KRAS介导的信号转导重新激活，代谢重新编程，上皮-间充质转化，以及肿瘤微环境的变化。这项优雅的研究展示了KRAS G12C抑制剂临床耐药性的多方面性质以及克服耐药性的潜在途径。
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.