Targeting IKRAS/I G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver

• Published in: International journal of molecular sciences 2024-03, Vol.25 (6)
• Main Authors: Ros, Javier, Vaghi, Caterina, Baraibar, Iosune, Saoudi González, Nadia, Rodríguez-Castells, Marta, García, Ariadna, Alcaraz, Adriana, Salva, Francesc, Tabernero, Josep, Elez, Elena
• Format: Article
• Language: English
• Subjects: Amino acids; Antimitotic agents; Antineoplastic agents; Biotechnology industry; Cancer; Chemotherapy; Colorectal cancer; Comparative analysis; Development and progression; Genetic aspects; Pharmaceutical industry; Sarcoma; Trifluridine
• ISSN: 1422-0067
• DOI: 10.3390/ijms25063304

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.