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Ref Type Journal Article
PMID (21551259)
Authors Prazeres H, Couto JP, Rodrigues F, Vinagre J, Torres J, Trovisco V, Martins TC, Sobrinho-Simões M, Soares P
Title In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp.
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Abstract Text Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (RET) proto-oncogene. RET encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS-RAF-ERK1/2, PIK3-AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the RET variants and measured the number of NIH3T3 transformation foci and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1/2, STAT1, STAT3, and TCF4), and the extent of ERK1/2 inhibition on sorafenib treatment. We found that RET variants Arg886Trp and Glu511Lys have shown increased in vitro transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and Arg886Trp showed 10- and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5- and 3-fold versus 1.2- and 2-fold in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens.

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Molecular Profile Treatment Approach
RET C634S RET Inhibitor
RET C618G RET Inhibitor
RET C620Y RET Inhibitor
RET E632_L633del RET Inhibitor
RET C630Y RET Inhibitor
RET C634L RET Inhibitor
RET E574D RET Inhibitor
RET S409Y RET Inhibitor
RET T930K RET Inhibitor
RET R833C RET Inhibitor
RET T930P RET Inhibitor
RET V804M RET Inhibitor
RET T636M RET Inhibitor
RET C634Y RET Inhibitor
RET C630del RET Inhibitor
RET V804L RET Inhibitor
RET S904F RET Inhibitor
RET C618F RET Inhibitor
RET G607C RET Inhibitor
RET C515S RET Inhibitor
RET C609R RET Inhibitor
RET C630R RET Inhibitor
RET L633_C634dup RET Inhibitor
RET E768D RET Inhibitor
RET R912P RET Inhibitor
RET C611W RET Inhibitor
RET M918V RET Inhibitor
RET G533C RET Inhibitor
RET C515W RET Inhibitor
RET C618S RET Inhibitor
RET M918T RET Inhibitor
RET act mut RET Inhibitor
RET E616Q RET Inhibitor
RET S891A RET Inhibitor
RET E805K RET Inhibitor
RET S649L RET Inhibitor
RET C634F RET Inhibitor
RET C630G RET Inhibitor
RET C634W RET Inhibitor
RET M848T RET Inhibitor
RET C618Y RET Inhibitor
RET C620S RET Inhibitor
RET C609Y RET Inhibitor
RET I852M RET Inhibitor
RET C618R RET Inhibitor
RET C630F RET Inhibitor
RET E505_G506del RET Inhibitor
RET amp RET Inhibitor
RET V292M RET Inhibitor
RET D567Y RET Inhibitor
RET C634G RET Inhibitor
RET Y806C RET Inhibitor
RET C609S RET Inhibitor
RET R886W RET Inhibitor
RET K666E RET Inhibitor
RET Y606C RET Inhibitor
RET K666N RET Inhibitor
RET C531R RET Inhibitor
RET A883T RET Inhibitor
RET C620R RET Inhibitor
RET D631Y RET Inhibitor
RET C611Y RET Inhibitor
RET D898_E901del RET Inhibitor
RET D567N RET Inhibitor
RET D584N RET Inhibitor
RET A510V RET Inhibitor
RET C634R RET Inhibitor
RET E511K RET Inhibitor
RET C630S RET Inhibitor
RET C634_R635insHELC RET Inhibitor
RET A883F RET Inhibitor
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 R886W missense gain of function RET R886W lies within the protein kinase domain of the Ret protein (UniProt.org). R886W confers a gain of function to the Ret protein as demonstrated by increased Erk1/2, Stat1/3, and Tcf activation and transformation of cultured cells (PMID: 21551259).
RET S649L missense unknown RET S649L lies within the transmembrane domain of the Ret protein (UniProt.org). The functional effect of S649L is conflicting as it results in increased kinase activity and cell proliferation and moderate transforming activity in culture (PMID: 18322301), but in another study does not result in transforming activity in culture, leads to Ret pathway signaling similar to wild-type Ret in reporter assays (PMID: 21551259), and results in reduced ability to self-associate in culture (PMID: 23067224).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET R886W Advanced Solid Tumor sensitive Sorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing RET R886W were sensitive to treatment with Nexavar (sorafenib) in culture, demonstrating reduced cell proliferation (PMID: 21551259). 21551259