Farnesylation-driven KRAS phase separation promotes colon tumor growth.

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is one of the most frequently activated driver genes across human cancers. We identified a regulatory mechanism where KRAS forms condensates in the cytoplasm through liquid-liquid phase separation (LLPS), driven by farnesylation at the C185 residue within its hypervariable region (HVR). These condensates are associated with advanced stages and poor outcomes in colon cancer. Functionally, KRAS condensates efficiently interact with Ras-converting enzyme 1 (RCE1), promoting RCE1 clustering, enhancing KRAS processing, and facilitating its translocation to the plasma membrane, which amplifies KRAS signaling and promotes tumor growth. Growth factor stimulation further elevates KRAS condensate formation, emphasizing its role in tumor biology. Therapeutically, screening US Food and Drug Administration (FDA)-approved drugs revealed that statins, particularly pitavastatin, disrupt KRAS LLPS by inhibiting farnesylation, effectively suppressing colon cancer growth and enhancing the efficacy of G12Ci treatment. These findings uncover LLPS as a mechanism regulating KRAS activity and provide a promising target for therapeutic intervention.