Abstract 1096: Co-targeting of AKT and Pim kinases in mouse PTEN-deficient prostate cancer
Authors: Velasco Marco A. De , Sugimoto Koichi , Kura Yurie , Ando Naomi , Sato Noriko , Sakai Kazuko , Davies Barry R. , Huszar Dennis , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: July 2017

AKT and Pim kinases modulate programmed cell death by the phosphorylation of common substrates that regulate apoptosis and other survival processes. Evidence suggests that the antitumor effects of targeted Akt inhibition can be inhibited or diminished by the JAK/STAT-dependent induction of Pim kinases. In this study we examined the therapeutic potential of co-targeting AKT and Pim in a genetically engineered mouse model of prostate cancer driven by the conditional inactivation of PTEN. The antitumor effects of AZD5363, a pan AKT inhibitor, and AZD1208, a highly potent Pim kinase inhibitor, were investigated as monotherapy or in combination on mice harboring castration-naïve prostate tumors and mice that developed castration-resistant disease. Mice were randomized treated for four weeks. Safety and tolerability was assessed by bodyweight changes. Antitumor activity was determined by differences in tumor burden, proliferation and apoptosis and histology. Molecular activity was assessed by examining the phosphorylation of common substrates by western blot analysis. Treatments were well-tolerated and no significant differences in bodyweight changes were observed. In castration-naïve prostate tumors, treatments with AZD5363, AZD1208 and AZD5363/AZD1208 resulted in 11.9%, 13.5% and 36.9% reductions of tumor burden compared to vehicle treated controls, respectively, P&lt;0.001. The treatment combination of AZD5363/AZD1208 demonstrated significant antitumor activity compared to monotherapy, P&lt;0.001. In the castration-resistant tumors, treatments with AZD5363, AZD1208 and AZD5363/AZD1208 resulted in 21%, 9.5% and 27% reductions of tumor burden compared to vehicle treated controls, respectively, P&lt;0.004. Although the differences in in tumor burden were not statistically between monotherapy and combination therapy, a notable degree of tumor gland regression was observed in tumors treated with AZD5363/AZD1208. Overall, combination therapy showed a synergistic effect by inhibited or impaired phosphorylation of PRAS40, eIF4B and BAD in both castration-naïve and castration-resistant tumor models. Inhibition of both pathways enhanced the reduction of tumor cell proliferation and increased apoptosis. Overall, our findings provide in vivo data to support redundancy between AKT/Pim survival pathways and suggest that a therapeutic approach of combined AKT/Pim kinase inhibition may be possible therapeutic approach for AKT-driven prostate cancer.

Citation Format: Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Naomi Ando, Noriko Sato, Kazuko Sakai, Barry R. Davies, Dennis Huszar, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Co-targeting of AKT and Pim kinases in mouse PTEN-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1096. doi:10.1158/1538-7445.AM2017-1096