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0Research identifies a critical regulatory mechanism in which KRAS proteins form cytoplasmic condensates through a process called liquid-liquid phase separation (LLPS). This phenomenon is specifically driven by farnesylation, a hydrophobic modification at the C185 residue that enables KRAS to aggregate into membrane-less droplets. These condensates facilitate essential protein processing by clustering with enzymes at the endoplasmic reticulum, which ultimately promotes tumor growth and correlates with advanced stages of colon cancer. While growth factors stimulate the formation of these clusters, screening of FDA-approved drugs reveals that certain statins, such as pitavastatin, can disrupt this process by inhibiting farnesylation. Consequently, targeting the physical phase separation of KRAS suppresses cancer progression and improves the therapeutic efficacy of existing KRAS G12C inhibitors. This discovery positions biomolecular condensation as a vital new target for overcoming drug resistance in aggressive malignancies.
References:
Wang X, Zhang Y, Lu M, et al. Farnesylation-driven KRAS phase separation promotes colon tumor growth[J]. Cell, 2026.
