Abstract

ABSTRACT Background Spindle cell tumors with RET rearrangements exhibit variable clinical behaviors, ranging from benign to highly aggressive malignancies. The underlying heterogeneity is suspected to be associated with distinct fusion partner genes. Understanding the impact of these fusion partners on oncogenic potential is crucial for precision therapy. Methods We report a case of a spindle cell tumor harboring an MYH10::RET fusion, which initially responded to anti-RET therapy but relapsed due to an NTRK1 fusion. Isogenic cell lines expressing MYH10::RET and CCDC6::RET were established. Functional assays, including cell proliferation, migration, invasion, and kinase activity assays, were performed. Genomic profiling was conducted using targeted DNA and RNA NGS and FISH. Results MYH10::RET-expressing cells showed significantly higher proliferation, migration, and invasion compared to CCDC6::RET-expressing cells. MYH10::RET exhibited approximately three-fold higher kinase activity. The patient's disease was managed through sequential targeted therapies, including combination therapy with third-generation inhibitors targeting RET and NTRK. Conclusion Our findings suggest that distinct RET fusion partners significantly contribute to the clinical heterogeneity of RET-rearranged spindle cell tumors, likely through differential kinase activity. Continuous genomic monitoring is essential for identifying resistance mechanisms and guiding precision therapy. Future studies should explore the impact of different fusion partners on tumor behavior and therapeutic response.