MYC activity mitigates response to rapamycin in prostate cancer through 4EBP1-mediated inhibition of autophagy

Loss of PTEN and activation of PI3K are commonly observed in advanced prostate cancer. Inhibition of mTOR, a downstream target of PI3K 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 demonstrate 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 PrECs demonstrated selective increased expression of 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 re-sensitization 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.