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Ref Type Journal Article
PMID (36416226)
Authors Wijewardene A, Bastard K, Wang B, Gild M, Luxford C, Gill AJ, Robinson B, Bullock M, Clifton-Bligh R
Title A case report of poor response to Selpercatinib in the presence of a 632_633 RET deletion.
Abstract Text Genomic deletions in medullary thyroid cancer (MTC) are rare. Selpercatinib is a highly selective RET inhibitor for treatment of metastatic RET-altered MTC. We report a case of a 35 year old male with an aggressive metastatic MTC harboring p.632_633del RET poorly responsive to RET kinase inhibitor selpercatinib. Objective Understand the clinical phenotype of p.632_633del RET in MTC in context of novel RET kinase inhibitor treatment.Wild-type and p.632_633del RET 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 analysed on luciferase assays.Structural modeling revealed the paucity of disulfide bridge between Cys630-Cys634 in p.632_633del RET 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 RET that hosts selpercatinib. In vitro 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 suggest p.632_633del RET results inpoor response to selpercatinib.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET E632_L633del thyroid gland medullary carcinoma conflicting Selpercatinib Case Reports/Case Series Actionable In a clinical case study, Retevmo (selpercatinib) treatment resulted in limited activity in a patient with medullary thyroid carcinoma harboring RET E632_L633del, with a partial response achieved at cycle 9 but significant progressive disease observed at cycle 13 (PMID: 36416226; NCT03157128). 36416226
RET E632_L633del Advanced Solid Tumor conflicting Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing RET E632_L633del was less sensitive to Retevmo (selpercatinib) than cells expressing wild-type RET in culture (PMID: 36416226). 36416226
RET E632_L633del Advanced Solid Tumor conflicting Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, a cell line expressing RET E632_L633del was less sensitive to Gavreto (pralsetinib) than cells expressing wild-type RET in culture (PMID: 36416226). 36416226