Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Autophagy / drug effects*
-
Autophagy-Related Protein 5
-
Basic Helix-Loop-Helix Transcription Factors / metabolism
-
Carcinoma, Renal Cell / enzymology
-
Carcinoma, Renal Cell / genetics
-
Carcinoma, Renal Cell / metabolism
-
Carcinoma, Renal Cell / pathology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Dose-Response Relationship, Drug
-
Gene Expression Regulation, Neoplastic
-
Gene Silencing
-
Golgi Apparatus / metabolism
-
Humans
-
Hydrogen-Ion Concentration
-
Hypoxia-Inducible Factor 1 / metabolism
-
Inhibitory Concentration 50
-
Kidney Neoplasms / enzymology
-
Kidney Neoplasms / genetics
-
Kidney Neoplasms / metabolism
-
Kidney Neoplasms / pathology*
-
Male
-
Mice
-
Mice, SCID
-
Microtubule-Associated Proteins / metabolism
-
Molecular Structure
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Transport
-
Pyridines / pharmacology*
-
Structure-Activity Relationship
-
Thiazoles / pharmacology*
-
Time Factors
-
Transfection
-
Vacuoles / drug effects
-
Vacuoles / metabolism
-
Vacuoles / pathology
-
Von Hippel-Lindau Tumor Suppressor Protein / genetics
-
Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
-
Yeasts / drug effects
-
Yeasts / growth & development
-
Yeasts / metabolism
Substances
-
Antineoplastic Agents
-
Atg5 protein, mouse
-
Autophagy-Related Protein 5
-
Basic Helix-Loop-Helix Transcription Factors
-
Hypoxia-Inducible Factor 1
-
Microtubule-Associated Proteins
-
Pyridines
-
STF 62247
-
Thiazoles
-
endothelial PAS domain-containing protein 1
-
Von Hippel-Lindau Tumor Suppressor Protein
-
Phosphatidylinositol 3-Kinases