ena-STUDY-AZ-21-02-2014-15:40:18:453-283
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.
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.