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J. Biol. Chem., Vol. 282, Issue 40, 29230-29240, October 5, 2007

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Sorafenib Functions to Potently Suppress RET Tyrosine Kinase Activity by Direct Enzymatic Inhibition and Promoting RET Lysosomal Degradation Independent of Proteasomal Targeting^*

Iván Plaza-Menacho, Luca Mologni, Elisa Sala, Carlo Gambacorti-Passerini, Anthony I. Magee^¶, Thera P. Links^||, Robert M. W. Hofstra^**, David Barford, and Clare M. Isacke¹

From the Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, SW3 6JB London, United Kingdom, the Department of Clinical and Preventive Medicine, University Milano-Bicocca, 20052 Milan, Italy, the ^¶Section of Molecular and Cellular Medicine, Imperial College, SW7 2AZ London, United Kingdom, the ^||Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands, the ^**Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands, and the Section of Structural Biology, Institute of Cancer Research, SW3 6JB London, United Kingdom

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 IC₅₀ values of 5.9 and 7.9 nM, respectively. Interestingly, these values were 6–7-fold lower than the IC₅₀ 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 Val⁸⁰⁴ gatekeeper residue, MEN2 tumors may be less susceptible to acquired Sorafenib resistance.

Received for publication, April 25, 2007 , and in revised form, July 27, 2007.

^* This work was supported by the Breakthrough Breast Cancer, Ministry of Education and Science of Spain, the Medical Research Council, the Italian Association for Research on Cancer, and European Union Prokinase Network Grant 503467. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, UK. Tel.: 44-20-7153-5510; Fax: 44-20-7153-5340; E-mail: clare.isacke{at}icr.ac.uk.

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