Numerous mechanisms of resistance to direct KRAS G12C inhibition were revealed.

  • Major Finding: Numerous mechanisms of resistance to direct KRAS G12C inhibition were revealed.

  • Concept: Tissue-based molecular analyses were conducted on pre- and post-AMG510 treatment samples from a rapid-autopsy case.

  • Impact: A need is demonstrated for future rigorous evaluation of these resistance pathways in model systems.

KRAS G12C inhibitors represent a major breakthrough in targeting mutant KRAS in patients with lung cancer; however, response rates are short-lived due to acquired resistance. The underlying mechanisms behind this resistance remain to be fully elucidated; therefore, Tsai, Woodcock, and colleagues conducted deep RNA and whole-exome sequencing on matched normal, pretreatment, and posttreatment samples from a rapid autopsy case of a patient with KRASG12C-mutant lung adenocarcinoma who demonstrated initial response but quickly developed resistance to the KRAS G12C inhibitor AMG510. Posttreatment samples displayed robust MAPK pathway activation as well as upregulation of pathways involving YAP1. Furthermore, upregulation of gene sets involved in hedgehog, NOTCH and WNT, TGF-β, epithelial–mesenchymal transition, and tumor angiogenesis were observed, as were notable increases in fatty and bile acid metabolism, adipogenesis, and myogenesis. An increase in xenobiotic metabolism was also noted, which alludes to the ability of tumors to reduce intracellular levels of AMG510. Conversely, G2M checkpoint and E2F target gene sets were downregulated in posttreatment samples. The mutant allele frequency for KRAS G12C mutations was found to be decreased in a large portion of posttreatment samples; however, no new mutations in KRAS or mutations in MAPK signaling that would lead to its reactivation were discovered. Further analyses demonstrated that KRAS G12C copy-number loss was not a likely mediator of resistance, and clonal populations of metastatic lesions exhibit different mechanisms of resistance. Immunogenomic analysis of posttreatment samples indicated reduction in gene signatures associated with T- and B-cell function as well as an increase in mast cell populations and a decrease in the number of predicted neoantigens. These results suggest the immune editing of tumor clones concurrent with AMG510 treatment as well as the development of resistant tumors that had become immunologically “cold.” Overall, this study reveals the presence of multiple mechanisms of resistance to KRAS G12C inhibition and suggests the need for further validation and understanding of these methods of escape.

Tsai YS, Woodcock MG, Azam SH, Thorne LB, Kanchi KL, Parker JS, et al. Rapid idiosyncratic mechanisms of clinical resistance to KRAS G12C inhibition. J Clin Invest 2022 Jan 6 [Epub ahead of print].

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