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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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research			2022 Sep 27	3751-3762	Cancer Res

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
No data available in table

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
No data available in table

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
No data available in table

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Showing 1 to 10 of 10 entries

Gene	Variant	Impact	Protein Effect	Variant Description
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	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	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	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	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).
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	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	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).

Showing 1 to 10 of 10 entries

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Showing 1 to 24 of 24 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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 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 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 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
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 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 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 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 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 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 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 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 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 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 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 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 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 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

Showing 1 to 24 of 24 entries

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