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PIM Kinase Inhibitor AZD1208 Treats MYC-driven Prostate Cancer

Identifiers: SRA: ERP004944
BioProject: PRJEB5525
AZ: ena-STUDY-AZ-21-02-2014-15:40:18:453-283
Study Type: 
Population Genomics
Abstract: 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.
Description: 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.

Related SRA data

Experiments:
12 ( 12 samples )
Runs:
12 (75.6Gbp; 53.3Gb)
Additional objects:
File type count
fastq 24
assembled contigs 2