Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Endocrine-related cancer	18	4	2011 Aug	401-12	Endocr Relat Cancer

URL

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 C611W	RET Inhibitor
RET C634Y	RET Inhibitor
RET T636M	RET Inhibitor
RET Y806C	RET Inhibitor
RET C634R	RET Inhibitor
RET V804L	RET Inhibitor
RET C634F	RET Inhibitor
RET C618R	RET Inhibitor
RET E511K	RET Inhibitor
RET A510V	RET Inhibitor
RET V292M	RET Inhibitor
RET G533C	RET Inhibitor
RET M918V	RET Inhibitor
RET E616Q	RET Inhibitor
RET C630R	RET Inhibitor
RET C609Y	RET Inhibitor
RET K666E	RET Inhibitor
RET S904F	RET Inhibitor
RET I852M	RET Inhibitor
RET V804M	RET Inhibitor
RET C630S	RET Inhibitor
RET Y606C	RET Inhibitor
RET C515W	RET Inhibitor
RET act mut	RET Inhibitor
RET C630F	RET Inhibitor
RET C620S	RET Inhibitor
RET D567N	RET Inhibitor
RET E805K	RET Inhibitor
RET D567Y	RET Inhibitor
RET M848T	RET Inhibitor
RET R886W	RET Inhibitor
RET A883T	RET Inhibitor
RET C634S	RET Inhibitor
RET S409Y	RET Inhibitor
RET C515S	RET Inhibitor
RET C630G	RET Inhibitor
RET C618F	RET Inhibitor
RET C531R	RET Inhibitor
RET L633_C634dup	RET Inhibitor
RET S891A	RET Inhibitor
RET M918T	RET Inhibitor
RET C634W	RET Inhibitor
RET R912P	RET Inhibitor
RET D631Y	RET Inhibitor
RET E768D	RET Inhibitor
RET A883F	RET Inhibitor
RET C618S	RET Inhibitor
RET D584N	RET Inhibitor
RET T930P	RET Inhibitor
RET C609R	RET Inhibitor
RET E574D	RET Inhibitor
RET S649L	RET Inhibitor
RET C618Y	RET Inhibitor
RET D898_E901del	RET Inhibitor
RET C634G	RET Inhibitor
RET C630Y	RET Inhibitor
RET C630del	RET Inhibitor
RET G607C	RET Inhibitor
RET C618G	RET Inhibitor
RET C634L	RET Inhibitor
RET C611Y	RET Inhibitor
RET R833C	RET Inhibitor
RET C620Y	RET Inhibitor
RET C609S	RET Inhibitor
RET C620R	RET Inhibitor
RET E505_G506del	RET Inhibitor
RET E632_L633del	RET Inhibitor
RET T930K	RET Inhibitor
RET K666N	RET Inhibitor
RET C634_R635insHELC	RET Inhibitor
RET amp	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