RET fusion partners dictate oncogenic potential in undifferentiated spindle cell sarcomas

  • Cancer Biol Ther. 2026 Dec 31;27(1):2683190. doi: 10.1080/15384047.2026.2683190.
Qi Gui  1 ,  Ying Zhang  2  3 ,  Mei Yang  2  3 ,  Rongrui Liang  1  4 ,  Man Huang  1 ,  Xiaoshan Yang  2  3 ,  Nan Chen  2  3 ,  Xiaojun Chen  2  3 ,  Mengyao Wu  4 ,  Huafei Chen  2  3 ,  Lijun Meng  2  3 ,  Sheng Xiao  5 ,  Min Tao  1  2  4
Affiliations
  • 1. Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.
  • 2. Advanced Molecular Pathology Institute of Soochow University and SANO, Suzhou, China.
  • 3. Suzhou SANO Precision Medicine Ltd, SANO Medical Laboratories, Suzhou, China, Suzhou, China.
  • 4. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 5. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
PMID: 42240026 DOI: 10.1080/15384047.2026.2683190
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.

Keywords
MYH10::RET; NTRK1 fusion resistance; RET fusion heterogeneity; kinase activity disparity; sequential targeted therapy; undifferentiated spindle cell sarcoma.
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