Autophagy is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival during metabolic stress. Increasing evidence also suggests that autophagy is induced during therapeutic stress and is believed to promote drug resistance limiting the treatment efficacy of anticancer drugs. Our goal was to define the role of autophagy during prostate cancer tumorigenesis and determine the consequences of pharmacological intervention. We used a genetically engineered mouse model of prostate cancer that is based on the PSA-Cre driven inactivation of PTEN to show that autophagy is induced during tumor progression and the transformation to castration resistant prostate cancer. We also report that inhibition of autophagy by the conditional inactivation of ATG7, a gene essential for autophagosome formation, does not contribute to initiate prostate cancer. However, simultaneous inactivation of ATG7 and PTEN leads to suppressed tumor progression in castration-naïve and CRPC models. Additionally PTEN/ATG7 double gene knockout mice were more sensitive to targeted mTOR inhibition than PTEN single gene knockouts. Pharmacological inhibition of autophagy using the lysomotropic agent chloroquine synergized with everolimus to inhibit survival of human and mouse prostate cancer cells in vitro. Despite a strong antitumor activity in vitro, the combinations of everolimus and chloroquine failed to demonstrate any meaningful improvement over everolimus alone when tested in vivo with PTEN-mutant mice. In summary, our findings demonstrate that autophagy is required for prostate cancer progression and contributes to therapeutic resistance; however, pharmacological inhibition of autophagy, using a lysomotropic agent, was ineffective in producing a meaningful antitumor benefit in an autochthonous cancer system. Our preliminary findings suggest a need for further investigation before implementing the concept of autophagy inhibition into clinical trials.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. The role of autophagy in prostate tumorigenesis and its therapeutic implications. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3912. doi:10.1158/1538-7445.AM2014-3912

©2014 American Association for Cancer Research.
2014