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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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 |
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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 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 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 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 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 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 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 | 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 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 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 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 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 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 |
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 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 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 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 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 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 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 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 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 |