KRAS-targeted therapy in oncology: From four decades of failed attempts to a new era of precision medicine

Mutations in the KRAS (Kirsten Rat Sarcoma Viral Proto-oncogene) gene represent among the most prevalent oncogenic drivers in human malignancies, occurring in approximately 25% of all solid tumors. For more than four decades, KRAS was considered pharmacologically intractable due to the protein's picomolar affinity for GTP/GDP and the absence of accessible allosteric binding sites. The identification of the switch-II pocket (S-IIP) and subsequent development of mutation-selective covalent inhibitors targeting the KRAS G12C mutant fundamentally altered this paradigm. Sotorasib and adagrasib, the first approved KRAS G12C inhibitors, have demonstrated meaningful clinical activity in NSCLC and, in combination with anti-EGFR agents, in colorectal cancer. However, both drugs achieve only modest objective response rates of 30–43% in NSCLC with median progression-free survival of approximately six months, substantially below outcomes achieved with targeted therapies directed at EGFR or ALK. Acquired resistance emerges rapidly through on-target KRAS mutations, bypass signaling, and phenotypic plasticity. An expanding pipeline of next-generation agents targeting G12D, G12V, and pan-KRAS approaches offers the first plausible therapeutic options for pancreatic and other KRAS-driven cancers beyond G12C. This narrative review critically evaluates the biological basis of KRAS oncogenesis, the pharmacological obstacles that delayed drug development, the clinical performance and limitations of approved inhibitors, resistance mechanisms and rational combination strategies, and the evidence base and uncertainties surrounding next-generation therapeutic approaches.