Overcoming resistance to KRAS inhibition in KRAS/PIK3CA co-mutated colorectal cancer

Oncogenic PIK3CA in KRAS-mutant colorectal cancer cells promotes resistance to the pan-RAS inhibitor daraxonrasib (RMC-6236), linked to sustained PI3K-AKT signaling.

• Why it matters: KRAS inhibition shows limited benefit in colorectal cancer, and PI3K is a direct RAS effector that is co-mutated in about 45% of CRC cases.
• What they did: Using isogenic colorectal cancer cells engineered with two common activating PIK3CA mutations, the study profiled adaptive signaling by global phosphoproteomics after daraxonrasib treatment.
• The result: Combined RAS and PI3K inhibition suppressed both pathways and induced apoptosis in PIK3CA-mutant cells, supporting oncogenic PIK3CA as a resistance determinant in KRAS/PIK3CA co-mutant tumors.

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