Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer
Tadashi Manabe, Trever G. Bivona
Tadashi Manabe, Trever G. Bivona
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e156891. https://doi.org/10.1172/JCI156891.
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Commentary

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

Abstract

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.

Authors

Tadashi Manabe, Trever G. Bivona

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Figure 1

Schema showing the approach and main findings of Tsai et al.

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Schema showing the approach and main findings of Tsai et al. (9). Biopsy...
(9). Biopsy samples from a patient with KRAS G12C lung adenocarcinoma were taken before and after treatment with the KRAS G12C inhibitor, sotorasib. The patient was treated for 17 weeks and showed an initial response before developing acquired resistance. Whole-exome sequencing (WES) and RNA sequencing analyses of tumor and normal tissue samples showed KRAS-mediated signaling activation, YAP signaling, EMT activation, metabolic reprogramming, and TME changes that included coagulation, angiogenesis, and immune escape pathways.