Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Thyroid : official journal of the American Thyroid Association			2022 Nov 23	119-125	Thyroid

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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	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
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