A Case Report of Poor Response to Selpercatinib in the Presence of a 632_633 RET Deletion.

Genomic deletions in medullary thyroid cancer (MTC) are rare. Selpercatinib is a highly selective inhibitor for treatment of metastatic -altered MTC. We report a 35-year-old male with an aggressive metastatic MTC harboring p.632_633del that was poorly responsive to kinase inhibitor selpercatinib. Our objective was to understand the clinical phenotype of p.632_633del in MTC in the context of novel kinase inhibitor treatment. Wild-type and p.632_633del sequences were modeled using a lighter version of the AlphaFold2 (AF2) software. Functional studies were performed on transfected HEK 293 cells (pCMV6-Entry, pCMV6-RET, or pCMV6-RET(p.632_633del) treated with inhibitors for 24 hours and analyzed on luciferase assays. Structural modeling revealed a paucity of disulfide bridge between Cys630-Cys634 in p.632_633del sequences, apparent in wild-type, while forming an intermolecular disulfide bridge between two Cys656. Proximity of juxtamembrane segments of each dimer may impede Tyr687 phosphorylation and stable conformation of intracellular that hosts selpercatinib. experiments confirmed a reduction in efficacy of selpercatinib upon p.632_633del RET compared with wild-type RET control. Clinical presentation together with structural modeling and functional studies suggests that p.632_633del results in poor response to selpercatinib.