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MYC Activity Mitigates Response to Rapamycin in Prostate Cancer through Eukaryotic Initiation Factor 4E–Binding Protein 1–Mediated Inhibition of Autophagy

¹ Duke Institute for Genome Sciences and Policy and ² Duke Comprehensive Cancer Center, Duke University; ³ Division of Medical Oncology, Department of Medicine, and ⁴ Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina; Departments of ⁵ Medical Oncology and ⁶ Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts; and ⁷ Broad Institute of Harvard and MIT, Cambridge, Massachusetts

Requests for reprints: Phillip G. Febbo, Duke Institute for Genome Sciences and Policy, Duke University Medical Center, 2175 CIEMAS Building, Durham, NC 27710. Phone: 919-668-4774; Fax: 919-668-4777; E-mail: phil.febbo{at}duke.edu.

Key Words: mTOR • rapamycin • MYC • autophagy • 4EBP • prostate cancer

Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E–binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy. [Cancer Res 2009;69(19):7803–10]