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Cancer Cell. 2008 Jul 8;14(1):90-102. doi: 10.1016/j.ccr.2008.06.004.

A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy.

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1
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.

PMID:
18598947
PMCID:
PMC2819422
DOI:
10.1016/j.ccr.2008.06.004
[Indexed for MEDLINE]
Free PMC Article

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