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Renal cell carcinomas (RCCs) are refractory to standard therapies. The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in 75% of RCCs. By screening for small molecules selectively targeting VHL-deficient RCC cells, we identified STF-62247. STF-62247 induces cytotoxicity and reduces tumor growth of VHL-deficient RCC cells compared to genetically matched cells with wild-type VHL. STF-62247-stimulated toxicity occurs in a HIF-independent manner through autophagy. Reduction of protein levels of essential autophagy pathway components reduces sensitivity of VHL-deficient cells to STF-62247. Using a yeast deletion pool, we show that loss of proteins involved in Golgi trafficking increases killing by STF-62247. Thus, we have found a small molecule that selectively induces cell death in VHL-deficient cells, representing a paradigm shift for targeted therapy.

Original publication

DOI

10.1016/j.ccr.2008.06.004

Type

Journal article

Journal

Cancer Cell

Publication Date

08/07/2008

Volume

14

Pages

90 - 102

Keywords

Animals, Antineoplastic Agents, Autophagy, Autophagy-Related Protein 5, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Line, Tumor, Cell Proliferation, Cell Survival, Dose-Response Relationship, Drug, Gene Expression Regulation, Neoplastic, Gene Silencing, Golgi Apparatus, Humans, Hydrogen-Ion Concentration, Hypoxia-Inducible Factor 1, Inhibitory Concentration 50, Kidney Neoplasms, Male, Mice, Mice, SCID, Microtubule-Associated Proteins, Molecular Structure, Phosphatidylinositol 3-Kinases, Protein Transport, Pyridines, Structure-Activity Relationship, Thiazoles, Time Factors, Transfection, Vacuoles, Von Hippel-Lindau Tumor Suppressor Protein, Yeasts