A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy.
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.
Turcotte
Sandra
S
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chan
Denise A
DA
Sutphin
Patrick D
PD
Hay
Michael P
MP
Denny
William A
WA
Giaccia
Amato J
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D015003:Yeasts / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D000071187:Autophagy-Related Protein 5; D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D011725:Pyridines; D013844:Thiazoles; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C495773:Atg5 protein, mouse; C530878:STF 62247