Direct KRAS Targeting in Pancreatic and Colorectal Cancer: Biology, Therapeutics, and Next-Generation Combinations

KRAS mutations are major oncogenic drivers in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), historically considered "undruggable." Recent breakthroughs in allele-specific covalent inhibitors, such as sotorasib and adagrasib targeting KRASG12C, have transformed this paradigm. In CRC, combinations with anti-EGFR antibodies have demonstrated significant clinical benefit, leading to guideline-recommended regimens for KRASG12C-mutant metastatic disease. In PDAC, where non-G12C alleles predominate, emerging G12D-selective agents (e.g., MRTX1133) and pan-mutant KRAS inhibitors (e.g., BI‑2493) offer promising therapeutic avenues. However, monotherapy efficacy is limited by rapid adaptive resistance via RTK-mediated feedback, stromal interactions, and transcriptional reprogramming. This review synthesizes the mechanistic basis, clinical progress, and resistance landscapes of direct KRAS inhibition in PDAC and CRC. We highlight the critical need for rational, tissue-specific combination strategies—including vertical pathway inhibition, synthetic-lethal partners, and immunomodulatory approaches—to achieve durable responses. Future progress hinges on integrating real-time biomarker profiling, such as ctDNA and spatial transcriptomics, to guide adaptive, precision combination therapies tailored to the dynamic clonal and microenvironmental evolution of KRAS-mutant tumors.