Therapeutics Targeting Mutant KRAS

Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRASG12C. These inhibitors, such as AMG 510 and MRTX849, show promise in early-phase studies. Nevertheless, combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.

Automated summary

Aberrations in the RAS viral oncogene are prevalent in human cancers, particularly in the KRAS isoform where point mutations in codon 12 are present in up to 80% of KRAS-mutant malignancies. Despite the lack of approved KRAS-targeted agents, new impetus in drug development is provided by covalent allosteric inhibitors that target a shallow pocket on the KRAS surface, such as AMG 510 and MRTX849. Combination strategies targeting resistance mechanisms have become crucial in the fight against KRAS-mutant tumors.