Reference Detail

Ref Type

Journal Article

PMID

(17664273)

Authors

Plaza-Menacho I, Mologni L, Sala E, Gambacorti-Passerini C, Magee AI, Links TP, Hofstra RM, Barford D, Isacke CM

Title

Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of biological chemistry	282	40	2007 Oct 05	29230-40	J Biol Chem

URL

Abstract Text

Germ line missense mutations in the RET (rearranged during transfection) oncogene are the cause of multiple endocrine neoplasia, type 2 (MEN2), but at present surgery is the only treatment available for MEN2 patients. In this study, the ability of Sorafenib (BAY 43-9006) to act as a RET inhibitor was investigated. Sorafenib inhibited the activity of purified recombinant kinase domain of wild type RET and RET(V804M) with IC(50) values of 5.9 and 7.9 nm, respectively. Interestingly, these values were 6-7-fold lower than the IC(50) for the inhibition of B-RAF(V600E). In cell-based assays, Sorafenib inhibited the kinase activity and signaling of wild type and oncogenic RET in MEN2 tumor and established cell lines at a concentration between 15 and 150 nm. In contrast, inhibition of oncogenic B-RAF- or epidermal growth factor-induced ERK1/2 phosphorylation required micromolar concentrations of Sorafenib demonstrating the high specificity of this drug in targeting RET. Moreover, prolonged exposure to Sorafenib resulted in inhibition of cell proliferation and RET protein degradation. Using lysosomal and proteasomal inhibitors, we demonstrate that Sorafenib induces RET lysosomal degradation independent of proteasomal targeting. Furthermore, we provide a structural model of the Sorafenib.RET complex in which Sorafenib binds to and induces the DFG(out) conformation of the RET kinase domain. These results strengthen the argument that Sorafenib may be effective in the treatment of MEN2 patients. In addition, because inhibition of RET is not impaired by mutation of the Val(804) gatekeeper residue, MEN2 tumors may be less susceptible to acquired Sorafenib resistance.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET C634R	Advanced Solid Tumor	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of cells expressing RET C634R in culture (PMID: 17664273).	17664273
RET M918T	Advanced Solid Tumor	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased proliferation of cells expressing RET M918T in culture (PMID: 17664273).	17664273
RET M918T	colorectal cancer	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of colorectal cancer cells harboring a RET M918T mutation in culture (PMID: 17664273).	17664273
RET S891A	Advanced Solid Tumor	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation in cells expressing RET S891A in culture (PMID: 17664273).	17664273
RET rearrange	papillary thyroid carcinoma	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and activation of downstream signaling, and decreased growth of papillary thyroid carcinoma cells harboring the RET/PTC1 oncogene in culture (PMID: 17664273).	17664273
RET C634W	thyroid gland carcinoma	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited RET phosphorylation and decreased growth of thyroid carcinoma cells harboring a RET C634W mutation in culture (PMID: 17664273).	17664273
RET mutant	cancer	sensitive	Sorafenib	Preclinical	Actionable	In a preclinical study, Nexavar (sorafenib) inhibited wild-type RET and RET mutations to prevent cell proliferation in cell culture (PMID: 17664273).	17664273