Chimeric Oncoproteins Enhance Native Kinase Activity to Drive Tumorigenesis via Phase-separated Cytoplasmic Condensates

Here we demonstrate that recurrent FGFR3-TACC3 (FT) fusion proteins undergo liquid-liquid phase separation (LLPS) to form cytoplasmic condensates, driving tumorigenesis in lung cancer and glioma. These condensates function as oncogenic signaling hubs, enhancing FGFR3 native kinase activity and promoting hyperactivation of the canonical MAPK/ERK pathway.

The coiled-coil domain of TACC3 is essential for condensate formation and the oncogenic potential of FT fusions. CKAP5 and AURKA are recruited to FT phase-separated condensates, thereby amplifying MAPK/ERK signaling and triggering AURKA/MYC oncogenic program. Dual pharmacological inhibition of FGFR3 and AURKA synergistically dissipates LLPS and impedes the growth of FT-driven tumors.