NTRK Fusion as an Acquired Mechanism of Resistance to Selpercatinib in RET Positive Thyroid Cancer

Background: Rearrangement during Transfection (RET) proto-oncogene is involved in the pathogenesis of various thyroid cancer subtypes and drugs that block the RET tyrosine kinase pathways are used in the management of locally advanced and metastatic Medullary Thyroid Cancer (MTC). Acquired resistance to RET inhibitors likely occurs via two different mechanisms: (1) On-target mutations that prevent drug binding and (2) Activated alternative mechanisms which bypass the targeted kinase. We present a unique mechanism of selpercatinib resistance via secondary NTRK fusion mutation in a case of RET altered medullary thyroid cancer. Case Presentation: The patient is a 72-year-old female with stage III metastatic MTC who developed recurrence with newly found RET mutation 7 years after complete surgical resection. Despite initial stable response with selpercatinib for 2 years she rapidly progressed with widespread disease. Cell-free DNA (cfDNA) testing done at the time of progression revealed an NTRK1 fusion. Unfortunately, the patient succumbed to the disease despite starting targeted therapy with larotrectinib. Conclusion: This case highlights the importance of further investigation into mechanisms of resistance to RET inhibitors and drug studies directed towards overcoming them