PIM Kinase Inhibitor AZD1208 Treats MYC-driven Prostate Cancer

PIM1 kinase is coexpressed with MYC in human prostate cancers and dramatically enhances MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM kinase inhibitor, AZD1208, on prostate tumorigenesis and recurrence. AZD1208 treatment inhibited tumorigenesis in a c-MYC/Pim1-transduced tissue recombination model, in the Myc-CaP allograft model, and in several human prostate cancer xenografts. RNA-sequencing showed that AZD1208 inhibited multiple pro-tumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induce PIM1in prostate cancer cells and AZD1208 can act as a radiation sensitizer. Recurrent prostate tumors post-castration respond transiently to either AZD1208 or radiation treatment but the combination resulted in more sustained inhibition of tumor growth. Gene expression analysis of cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of p53 target genes. Notably, AZD1208-treated tumors that also received radiation robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Additionally, an AZD1208-resistant tumor gene signature was associated with biochemical recurrence in prostate cancer patients. These results indicate that PIM kinase inhibition is a valid treatment for MYC-driven prostate cancers and combining AZD1208 with activators of the p53 pathway such as radiation may enhance treatment efficacy.