Targeting KRAS in Cancer: Advances in Precision Oncology and Drug Development
TL;DR
These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy, however, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.
Abstract
KRAS is among the most commonly mutated oncogenes in human cancers, driving tumour initiation, progression, and therapeutic resistance through dysregulation of multiple signalling pathways. For many years, KRAS was regarded as an undruggable target because of its high affinity for guanosine nucleotides and the absence of suitable drug-binding pockets. Recent advances in structural biology and medicinal chemistry have fundamentally changed this perspective, enabled the development of mutation-specific inhibitors and established KRAS as a clinically actionable target in precision oncology. The discovery of the switch-II binding pocket facilitated the design of selective covalent inhibitors targeting KRAS G12C, leading to the clinical approval of sotorasib and adagrasib for selected patients with KRAS G12C-mutated malignancies. These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy. However, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.