The evolving landscape of KRAS-targeted therapy: mechanisms of resistance and emerging strategies

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic drivers in human cancer and are associated with poor prognosis, limited therapeutic options, and frequent resistance to standard treatments. The approval of the first direct KRAS G12C inhibitors demonstrated that mutant KRAS can be targeted clinically, but their efficacy is restricted to a narrow allelic subset and is limited by adaptive resistance. This review summarizes recent advances in KRAS-targeted drug development beyond G12C and outlines emerging strategies designed to improve therapeutic outcomes. A comprehensive literature review was conducted using preclinical and clinical data from studies investigating KRAS inhibitors, rat sarcoma (RAS) pathway modulators, and rational drug combinations. Particular attention was given to allele-specific agents, pan-RAS inhibitors, feedback signaling mechanisms, and resistance biology. Next-generation KRAS inhibitors targeting non-G12C alleles, including KRAS G12D selective agents, have demonstrated potent preclinical activity but remain susceptible to feedback mitogen-activated protein kinase (MAPK) reactivation. Pan-RAS inhibitors that bind the active RAS-GTP state show activity across multiple alleles and tumor types, although toxicity and therapeutic window remain key concerns. Indirect strategies targeting SHP2, SOS1, and downstream MAPK components enhance pathway suppression and delay resistance, especially in combination with direct KRAS inhibitors. Resistance mechanisms encompass secondary KRAS mutations, bypass signaling through alternative RAS isoforms, and activation of parallel pathways. Comutations such as STK11 or KEAP1 further influence therapeutic response and immune contexture. KRAS-directed therapy is rapidly expanding beyond G12C, with allele-specific inhibitors, pan-RAS approaches, and rational combinations offering new opportunities for broader clinical benefit. Ongoing challenges include toxicity management, resistance evolution, and the development of predictive biomarkers to guide therapy selection.