The response of ETV6-NTRK3 condensates to TRK inhibitors elucidates their precise phase separation mechanism

NTRK fusion oncoproteins are considered to mediate oncogenesis in multiple rare cancers. These fusion oncoproteins form cytoplasmic kinase condensates to hyper-activate downstream signaling pathways. However, their responses to TRK inhibitors have not been investigated. Here we show that TRK inhibitors induce a quantity increasement and liquid-to-solid transition of ETV6-NTRK3 condensates. During this process, the ETV6-NTRK3 condensates undergo rapid dissolution and subsequent reemergence, with entirely altered components. We proposed a novel phase separation model for ETV6-NTRK3 that both ETV6 and NTRK3 fragments contribute to the condensate’s formation. These findings refresh the understanding of the phase separation mechanism of NTRK fusion proteins and provide basis for phenotype-based TRK inhibitor screening strategy.