The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30-40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC. Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms. Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors. Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival.