From undruggable to actionable: advances in KRAS targeting in colorectal cancer

KRAS (Kristen rat sarcoma viral oncogene homolog) mutations occur in approximately 40–50% of metastatic colorectal cancer (CRC) cases and have long been associated with resistance to anti-epidermal growth factor receptor (EGFR) therapies and poor clinical outcomes. Historically considered “undruggable”, KRAS has recently become a viable therapeutic target following the development of allele-specific inhibitors. The approval of KRAS G12C inhibitors such as sotorasib and adagrasib represents a major milestone, demonstrating clinical activity and improved outcomes compared with standard therapies in the molecularly defined subset. However, single-agent activity remains modest in CRC due to adaptive resistance mechanisms, including compensatory activation of EGFR and downstream signalling pathways. Combination strategies, particularly co-targeting of EGFR and KRAS G12C, have shown enhanced efficacy and are redefining treatment paradigms. Beyond G12C, newer approaches aim to broaden therapeutic coverage through next-generation KRAS inhibitors, pan-RAS or RAS(ON) inhibitors, and allele-specific agents targeting KRAS G12D and KRAS G12V. Additional strategies incorporating Src homology region 2-containing protein tyrosine phosphatase-2 (SHP2), son of sevenless homolog 1 (SOS1), or mitogen-activated protein kinase (MEK) inhibition, as well as emerging immune-based therapies, hold promise in overcoming resistance and improving durability of response. This review summarises recent advances in targeting KRAS-mutant CRC, explores mechanisms of therapeutic resistance, and highlights ongoing efforts to expand precision-based strategies across diverse KRAS alterations.