A Comprehensive Review of Allosteric KRAS-G12C Inhibitors: Structure, Mechanism of Action, Challenges, and Therapeutic Development Perspectives

Abstract

Context: KRAS-G12C has emerged as a clinically tractable oncogenic RAS mutation, establishing a new paradigm for allele-specific precision oncology. Covalent allosteric inhibitors, including sotorasib and adagrasib, have demonstrated meaningful clinical activity, particularly in advanced non-small cell lung cancer. However, intrinsic and acquired resistance limit their therapeutic efficacy. This review classifies key KRAS-G12C inhibitors according to their chemical scaffolds and binding modes, examines molecular and clinical mechanisms of resistance, and discusses emerging therapeutic strategies and future directions. Evidence Acquisition: Searches were conducted in Google Scholar and the National Center for Biotechnology Information, including PubMed where applicable. Reference lists of relevant articles were also screened to identify additional publications. Results: Current covalent KRAS-G12C inhibitors bind to the inducible switch II pocket and irreversibly stabilize the inactive guanosine diphosphate (GDP)-bound conformation, thereby suppressing downstream signaling. Resistance involves heterogeneous mechanisms, including secondary KRAS alterations, activation of bypass receptor tyrosine kinase pathways, reactivation of RAS–ERK and phosphatidylinositol 3-kinase (PI3K)–AKT signaling, and adaptive remodeling of the tumor microenvironment. Emerging approaches include next-generation covalent and noncovalent KRAS-G12C inhibitors, pan-KRAS and pan-RAS strategies, and inhibitors of Son of Sevenless homolog 1 (SOS1) and Src homology 2 domain-containing phosphatase 2 (SHP2). Rational combination regimens aim to improve therapeutic responses by simultaneously targeting upstream, downstream, and parallel survival pathways. Conclusions: KRAS-G12C inhibition represents a major advance in precision oncology, although resistance remains a central challenge. Further progress will depend on integrating improved inhibitor design with a deeper understanding of resistance biology and rational combination strategies to enhance the depth and durability of clinical responses.