Resistant KRAS(G12C) Inhibitor Subclones Exhibit Heterogeneous Alterations

Newly developed inhibitors targeting KRAS(G12C) have shown great promise, but potential resistance mechanisms are still under investigation. Zhao, Murciano-Goroff, Xue, Ang, and colleagues utilized paired liquid and/or tissue biopsies from 43 KRAS(G12C) inhibitor (G12Ci)-treated patients to gain genetic insight into the basis of resistance. No significant differences to baseline alterations were observed between exceptional responders and the rest of the cohort. However, in 27 of the 43 patients, treatment-induced alterations were identified and included secondary RAS alterations such as additional KRAS mutations or copy number gain, mutations in NRAS, non-V600E BRAF mutations, and other events including alterations to EGFR, FGFR2, MET, MYC, and IDH1/2. Lung and colorectal cancer patient-derived xenograft-bearing mice as well as isogenic cell lines with acquired resistance were used to gain additional insight into resistance mechanisms. Both models indicated secondary RAS mutations, as well as BRAF mutations, as critical variants in resistant models with a several-fold increase in secondary RAS mutations in the G12Ci treatment group as compared to the untreated group. To assess if these secondary mutations, either in RAS or BRAF, are enough to induce G12Ci resistance, drug-sensitive cells were engineered to express doxycycline-inducible mutants and, upon their expression, inhibition of downstream signaling was found to be attenuated as were the anti-proliferative effects, but target engagement by the drug remained unaffected. CRISPR-Cas9 screens were used to identify other vulnerabilities in these resistant cells and identified the depletion of several ERK signaling intermediates such as SHOC2, ERK2, NRAS, CRAF, and BRAF after G12Ci treatment. Combination treatments of G12Ci along with inhibitors of MEK, ERK, or RAF dimerization led to a more pronounced anti-proliferative effect in the presence of secondary mutations as compared to single therapy alone. This study reports heterogeneous genetic resistance alterations that emerge with KRAS(G12C) inhibitor treatment with the lack of a dominant resistance alteration suggesting the need for future biomarker-driven prospective clinical trials for patients who progress on G12Ci monotherapy.

Zhao Y, Murciano-Goroff YR, Xue JY, Ang A, Lucas J, Mai TT, et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature 2021;599:679–83.

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