KRAS Mutations in Cancers: From Undruggable Dilemma to Precision Medicine

ABSTRACT KRAS is one of the most frequently altered oncogenic drivers across human solid tumors and has long represented a central challenge in precision oncology. The clinical success of covalent KRAS G12C inhibitors has transformed a historically “undruggable” target into a tractable therapeutic class, but durable benefit remains limited by adaptive feedback, acquired resistance, co‐mutation context, and tumor‐lineage‐specific barriers. A major unresolved question is how to extend this success across diverse KRAS alleles and cancer types. This review summarizes the molecular epidemiology and therapeutic landscape of KRAS‐mutant cancers, with emphasis on non‐small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. We compare G12C‐directed therapy with emerging G12D‐, G12V‐, and pan‐KRAS strategies and dissect resistance architectures involving EGFR feedback, RTK/MAPK/PI3K pathway reactivation, phenotypic plasticity, stromal constraints, and immune or metabolic adaptation. We further discuss resistance‐informed combination therapy, targeted protein degraders, immune‐based approaches, antibody–drug conjugates, biomarker‐guided sequencing, and strategies for rare KRAS variants. Particular attention is given to how allele identity, tumor lineage, and adaptive signaling jointly shape therapeutic vulnerability. By framing KRAS therapy through the “same mutation, different outcomes” paradigm, this review provides a context‐informed roadmap for extending KRAS‐directed precision oncology beyond G12C monotherapy.