Reference Detail

Ref Type

Journal Article

PMID

(33161056)

Authors

Subbiah V, Shen T, Terzyan SS, Liu X, Hu X, Patel KP, Hu M, Cabanillas M, Behrang A, Meric-Bernstam F, Vo PTT, Mooers BHM, Wu J

Title

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology	32	2	2021 02	261-268	Ann Oncol

URL

Abstract Text

Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation.RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft.RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

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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
RET	G810C	missense	unknown	RET G810C lies within the protein kinase domain of the Ret protein (UniProt.org). G810C is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000, PMID: 33161056), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).	Y
RET	G810R	missense	unknown	RET G810R lies within the protein kinase domain of the Ret protein (UniProt.org). G810R is associated with RET inhibitor resistance in the context of RET fusions (PMID: 31988000, PMID: 33161056, PMID: 34373541), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jun 2024).	Y
RET	V738A	missense	unknown	RET V738A lies within the protein kinase domain of the Ret protein (UniProt.org). V738A has been demonstrated to confer drug resistance in the context of KIF5B-RET in culture (PMID: 29908090, PMID: 33161056), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET V804M RET G810C RET M918T	Advanced Solid Tumor	resistant	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing RET V804M, G810C, and M918T were resistant to Retevmo (selpercatinib) treatment in culture (PMID: 33161056).	33161056
RET M918T	Advanced Solid Tumor	sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited cell growth and Ret phosphorylation in transformed cells expressing RET M918T in culture (PMID: 33161056).	33161056
RET V804M RET M918T	Advanced Solid Tumor	predicted - sensitive	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Retevmo (selpercatinib) inhibited cell growth and Ret phosphorylation in transformed cells expressing RET V804M and M918T in culture (PMID: 33161056).	33161056
RET V804M RET G810S RET M918T	Advanced Solid Tumor	resistant	Selpercatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing RET V804M, G810S, and M918T were resistant to Retevmo (selpercatinib) treatment in culture (PMID: 33161056).	33161056