An overview of KRAS-targeting therapies for colorectal cancer in phase I and II development

KRAS mutations are among the most common oncogenic alterations in colorectal cancer (CRC). These mutations play a central role in tumor initiation and progression through activation of the MAPK signaling pathway. For many years, KRAS was considered an undruggable target. However, recent advances have led to the development of allele-specific inhibitors and combination strategies that directly target KRAS-driven signaling.

This review summarizes KRAS biology and pathway signaling; the prognostic and predictive impact of KRAS variants in CRC; and the emerging therapeutic landscape focused on phase I - II assets. We cover direct KRAS inhibitors (including G12C and non-G12C programs), pan-KRAS/'RAS-ON' and SOS1/SHP2 strategies, vertical MAPK/PI3K co-inhibition, metabolic and ferroptosis approaches, and translational immuno-oncology (checkpoint blockade in MSI-H/dMMR disease, cellular therapies, and vaccines). We also outline ongoing clinical trials, resistance mechanisms, biomarker considerations (tumor sidedness, co-mutations), and practical implications for sequencing and combinations.

KRAS-targeted therapy in CRC is entering a clinically actionable era. Allele-specific inhibitors are likely to find their place in combinations that suppress adaptive bypass (e.g. SOS1/SHP2, MEK/ERK, EGFR) while leveraging immunotherapy or metabolic vulnerabilities. Prospective biomarker integration and resistance-informed trial designs will be decisive in translating early signals into durable patient benefit.