Molecular landscape of KRAS G12C inhibitor resistance and rational combination strategies in cancer therapy

Abstract

Background: Oncogenic alterations in KRAS are among the most frequent driver mutations in human cancers, particularly lung, colorectal, and pancreatic cancers. Mutant KRAS was historically considered an “undruggable” target because of its high affinity for guanosine triphosphate and guanosine diphosphate (GDP) and the absence of readily druggable binding pockets. However, the “undruggable” paradigm shifted following the discovery of mutation-selective covalent inhibitors that target the KRAS G12C mutant. These inhibitors selectively target the inactive GDP-bound form of KRAS G12C through covalent binding to the mutant cysteine residue at codon 12. Despite their clinical activity, intrinsic and acquired resistance limit the efficacy and durability of KRAS G12C inhibitors. Resistance mechanisms include secondary KRAS mutations, activation of bypass signaling pathways, reactivation of MAPK/PI3K signaling, feedback pathway activation, epithelial–mesenchymal transition, metabolic reprogramming, and tumor-microenvironment protection. Aim: This review provides a thorough investigation into the molecular mechanisms of resistance to KRAS G12C inhibitors through an examination of recent clinical and preclinical evidence. This review also discusses emerging therapeutic approaches, including next-generation KRAS inhibitors, rational combination strategies, and interventions targeting adaptive signaling. Conclusion: Understanding the evolutionary mechanisms by which KRAS-mutant cancers evade targeted therapies is important for developing durable treatment strategies. Relevance for patients: Advances in molecular diagnostics and KRAS-targeted therapies may improve patient selection and outcomes with personalized treatments.