Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2022-02, Vol.132 (4)
Main Authors: Manabe, Tadashi, Bivona, Trever G
Format: Article
Language:English
Subjects:
Acetonitriles
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Ecosystem
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Piperazines
Proto-Oncogene Proteins p21(ras) - genetics
Pyrimidines
Tumor Microenvironment - genetics
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI156891