Reference Detail

Ref Type

Journal Article

PMID

(36416226)

Authors

Wijewardene A, Bastard K, Wang B, Gild M, Luxford C, Gill A, 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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Thyroid : official journal of the American Thyroid Association	33	1	2023 Jan	119-125	Thyroid

URL

Abstract Text

Background: 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 35-year-old male with an aggressive metastatic MTC harboring p.632_633del RET that was poorly responsive to RET kinase inhibitor selpercatinib. Objective: Our objective was to understand the clinical phenotype of p.632_633del RET in MTC in the context of novel RET kinase inhibitor treatment. Methods: 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 analyzed on luciferase assays. Results: Structural modeling revealed a 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. Conclusion: Clinical presentation together with structural modeling and functional studies suggests that p.632_633del RET results in poor 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	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
RET E632_L633del	medullary thyroid 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