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Ref Type Journal Article
PMID (36166639)
Authors Tabata J, Nakaoku T, Araki M, Yoshino R, Kohsaka S, Otsuka A, Ikegami M, Ui A, Kanno SI, Miyoshi K, Matsumoto S, Sagae Y, Yasui A, Sekijima M, Mano H, Okuno Y, Okamoto A, Kohno T
Title Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis.
URL
Abstract Text Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico-driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations.Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.

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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 C620R missense gain of function RET C620R lies within the extracellular domain of the Ret protein (PMID: 9230192). C620R results in decreased cell surface Ret expression, but also results in increased Ret and Shc phosphorylation, activation of transcription in a reporter assay, transformation in cell culture (PMID: 9879991, PMID: 9230192), increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
RET D567N missense gain of function RET D567N lies within the extracellular domain of the Ret protein (UniProt.org). D567N results in increased phosphorylation of Ret and Erk, IL3-independent growth in culture, and tumor formation in a mouse model (PMID: 36166639).
RET D567Y missense gain of function RET D567Y lies within the extracellular domain of the Ret protein (UniProt.org). D567Y results in increased phosphorylation of Ret and Erk, IL3-independent growth in culture, and tumor formation in a mouse model (PMID: 36166639).
RET D571N missense gain of function RET D571N lies within the extracellular domain of the Ret protein (UniProt.org). D571N confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
RET D584N missense gain of function RET D584N lies within the extracellular domain of the Ret protein (UniProt.org). D584N confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
RET D631Y missense gain of function RET D631Y lies within the extracellular domain of the Ret protein (UniProt.org). D631Y confers a gain of function on the Ret protein as demonstrated by induction of covalent Ret dimerization and phosphorylation (PMID: 10049754), increased Erk phosphorylation (PMID: 36166639), and transformation of cultured cells (PMID: 10049754, PMID: 36166639).
RET E574D missense gain of function RET E574D lies within the extracellular domain of the Ret protein (UniProt.org). E574D confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
RET G533C missense gain of function RET G533C lies within the extracellular domain of the Ret protein (UniProt.org). G553C results in increased Erk phosphorylation (PMID: 36166639) and Ret autophosphorylation, enhanced cell proliferation, micronuclei formation, and colony formation, decreased apoptosis and expression of thyroid-specific genes in culture (PMID: 21834681), transformation in culture (PMID: 36166639), and increased liver metastasis in mouse models (PMID: 21834681).
RET G607C missense gain of function RET G607C lies within the extracellular domain of the Ret protein (UniProt.org). G607C confers a gain of function to Ret as demonstrated by increased Erk phosphorylation and IL3-independent growth in culture (PMID: 36166639).
RET Y606C missense gain of function RET Y606C lies within the extracellular domain of the Ret protein (UniProt.org). Y606C results in ligand independent dimerization and constitutive phosphorylation of Ret, increased Erk2 phosphorylation (PMID: 18248647, PMID: 36166639), and transformation in culture (PMID: 36166639).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET C634R Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Ret signaling and viability in transformed cells expressing RET C634R in culture and inhibited tumor growth in a cell line xenograft model (PMID: 36166639). 36166639
RET D631Y Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited viability in transformed cells expressing RET D631Y in culture (PMID: 36166639). 36166639
RET C620R Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited viability in transformed cells expressing RET C620R in culture (PMID: 36166639). 36166639
RET G607C Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited viability in transformed cells expressing RET G607C in culture (PMID: 36166639). 36166639
RET D567N Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Ret signaling and viability in transformed cells expressing RET D567N in culture and inhibited tumor growth in a cell line xenograft model (PMID: 36166639). 36166639
RET D567Y Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Ret signaling and viability in transformed cells expressing RET D567Y in culture and inhibited tumor growth in a cell line xenograft model (PMID: 36166639). 36166639
RET M918T Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited viability in transformed cells expressing RET M918T in culture (PMID: 36166639). 36166639
RET D584N Advanced Solid Tumor sensitive Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Ret signaling in transformed cells expressing RET D584N in culture (PMID: 36166639). 36166639
RET D567Y Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Ret signaling and viability in transformed cells expressing RET D567Y in culture and inhibited tumor growth in a cell line xenograft model (PMID: 36166639). 36166639
RET D631_L633delinsE Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited viability in transformed cells expressing RET D631_L633delinsE in culture (PMID: 36166639). 36166639
RET M918T Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited viability in transformed cells expressing RET M918T in culture (PMID: 36166639). 36166639
RET E574D Advanced Solid Tumor sensitive Pralsetinib Preclinical - Biochemical Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Ret signaling in transformed cells expressing RET E574D in culture (PMID: 36166639). 36166639
RET C634R Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Ret signaling and viability in transformed cells expressing RET C634R in culture and inhibited tumor growth in a cell line xenograft model (PMID: 36166639). 36166639
RET D567N Advanced Solid Tumor sensitive Pralsetinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Ret signaling and viability in transformed cells expressing RET D567N in culture and inhibited tumor growth in a cell line xenograft model (PMID: 36166639). 36166639
RET E574D Advanced Solid Tumor sensitive Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Ret signaling in transformed cells expressing RET E574D in culture (PMID: 36166639). 36166639
RET E632_L633del Advanced Solid Tumor conflicting Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited viability in transformed cells expressing RET E632_L633del in culture (PMID: 36166639). 36166639
RET E632_L633del Advanced Solid Tumor conflicting Pralsetinib Preclinical - Cell culture Actionable In a preclinical study, Gavreto (pralsetinib) inhibited viability in transformed cells expressing RET E632_L633del in culture (PMID: 36166639). 36166639
RET G607C Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited viability in transformed cells expressing RET G607C in culture (PMID: 36166639). 36166639
RET D584N Advanced Solid Tumor sensitive Pralsetinib Preclinical - Biochemical Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Ret signaling in transformed cells expressing RET D584N in culture (PMID: 36166639). 36166639
RET D571N Advanced Solid Tumor sensitive Pralsetinib Preclinical - Biochemical Actionable In a preclinical study, Gavreto (pralsetinib) inhibited Ret signaling in transformed cells expressing RET D571N in culture (PMID: 36166639). 36166639
RET D571N Advanced Solid Tumor sensitive Selpercatinib Preclinical - Biochemical Actionable In a preclinical study, Retevmo (selpercatinib) inhibited Ret signaling in transformed cells expressing RET D571N in culture (PMID: 36166639). 36166639
RET D631Y Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited viability in transformed cells expressing RET D631Y in culture (PMID: 36166639). 36166639
RET C620R Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited viability in transformed cells expressing RET C620R in culture (PMID: 36166639). 36166639
RET D631_L633delinsE Advanced Solid Tumor sensitive Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, Retevmo (selpercatinib) inhibited viability in transformed cells expressing RET D631_L633delinsE in culture (PMID: 36166639). 36166639