Inhibition of both mutant and wild-type RAS-GTP in KRAS G12C colorectal cancer through cotreatment with G12C and EGFR inhibitors

Abstract

Multiple KRAS G12C inhibitors are in development, and the identification of effective combination treatment regimens should maximize the benefit these agents have on cancer patients. Here, we find that KRAS G12C heterozygous mutated colorectal cancer cells are sensitive to targeting with EGFR therapeutic antibodies. We find that KRAS G12C is partially impaired in binding to tumor suppressor NF1 and also to RAF, and our computational simulations reveal how these deficiencies result in partial sensitivity to EGFR inhibition. For the combination of EGFR and G12C inhibitors we observe synergy and reductions in active forms of both wild-type and mutant RAS. Our simulations reveal the synergy involves both wild-type and mutant RAS. Overall, our work suggests that the addition of an EGFR inhibitor to a KRAS G12C inhibitor regimen should be further evaluated as a strategy for KRAS G12C colorectal cancer patients.

Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance

“…Evidence for this possibility comes from statins, HMG-CoA reductase inhibitors, which inhibit the mevalonate pathway by directly interfering with farnesylation processes [188]. In vitro trials using CRC cells did show a synergis-tic effect when statins and EGFR monoclonal antibody were combined [189], but their use in clinical trials did not restore the sensitivity to cetuximab in patients harbouring RAS mutations [190].…”

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

“…Recently, a preclinical study has suggested synergism between cetuximab and AMG 510 in KRAS G12C mutated CRC, implying that the combination could be explored as an alternative approach. 79 Meanwhile, one can explore the upcoming results of different KRAS G12C inhibitors, as well as mutant-specific agents targeting more common variants such as KRAS G12D or G12V. 80 treating patients with rare genetic alterations Other than BRAF or HER2, even rarer genetic alterations in mCRC are now being considered as actionable targets.…”