In various types of malignancies, conventional forms of therapy such as surgery, radiation and chemotherapy are often ineffective. In the past decade, a convergence of scientific and technological advances has enabled the identification of molecular targets and signaling pathways specific to cancer cells, resulting in therapies with enhanced selectivity and efficacy and reduced toxicity. Protein kinases represent such molecular targets. We have recently shown that PRKD2 is a crucial regulator of tumor cell - endothelial cell communication in gastrointestinal tumors and demonstrated the kinase to be a novel regulator of glioblastoma growth. Here we report that HSP90/Cdc37 chaperone complex binds to and stabilizes PRKD2 in human cancer cells. RNAi-mediated ablation of HSP90 expression but also the pharmacological inhibition of the chaperone with two independent inhibitors induced degradation of PRKD2 in a broad range of human cancer cell lines and in vivo. Treatment of various cancer cell lines with proteasome inhibitors such as MG-132 or Bortezomib, followed by incubation with HSP90 inhibitors rescued the PRKD2 levels to the detergent-insoluble fraction suggesting that degradation of the kinase follows the proteasomal pathway. Kinetic experiments conducted with chaperone inhibitors demonstrated that PRKD2 was degraded in a time- and dose-dependent manner and this degradation was associated with the activation of the apoptotic programme both in vitro and in vivo. Furthermore, ectopic expression of the kinase protected cancer cells from the apoptotic effects of HSP90 abrogation suggesting PRKD2 as a protein whose depletion mediates the sensitivity of tumor cells to chaperone inhibition. Altogether, these findings 1) propose PRKD2 ablation through HSP90 inhibition as a potential therapeutic strategy with immediate implementation, 2) reveal the kinase as a crucial modulator of HSP90-mediated apoptotic effects and 3) promote the intensification of designing specific PRKD2 inhibitors and their implementation in targeted therapy in human cancer.

Citation Format: Ninel Azoitei, Kristina Diepold, Felicitas Genze, Arefeh Rouhi, Susanne Brobovich, Stefan Froehling, Gabriela Chiosis, Cornelia Brunner, Johan van Lint, Marcus Cronauer, Claudia Scholl, Thomas Seufferlein. Role of PRKD2 in HSP90 inhibition-mediated suppression of cancer growth. [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 5129. doi:10.1158/1538-7445.AM2014-5129

©2014 American Association for Cancer Research.
2014