Targeting Mutated KRAS Genes to Treat Solid Tumours.

Abstract

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.