Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver

Abstract

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer

“…Of note and in line with previous observations, both Sotorasib and BI-3406 showed robust on-target efficacy when applied as monotherapy in various assays using KRAS G12C mutant MiaPaCa pancreatic cancer cells that was further enhanced by concomitant MEK inhibition with Binimetinib, while efficacy of BI-2852 was limited. It is a novel observation in the study presented here that these KRAS plus MEK inhibitor combination regimens apparently show marked therapeutic synergism with concomitant irradiation across several of the in vitro assays presented here, suggesting this might pose a previously not recognized and therefore understudied scope for therapeutic synergism [ 58 , 62 ].…”

“…Increasing evidence suggests that identification of such combinatorial strategies aiming at synthetic lethality with oncogenic KRAS inhibition might be highly tissue-specific and vary with individual sites of tumor origin and with individual patterns of accompanying oncogenic genomic variants [ 57 ]. In KRAS G12C mutant colorectal cancer, combinatorial KRAS inhibition with Sotorasib and EGFR blockade by means of Panitumumab was found to be superior to either monotherapy in the phase 3 CodeBreaK300 trial, and similarly Adagrasib in combination with Cetuximab showed enhanced efficacy with considerably higher response rates as compared to monotherapy [ 58 ]. MEK and PI3K inhibition have previously been found to synergize and inhibit oncogenic KRAS signaling [ 59 ].…”