PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.

Kirschner AN, Wang J, van der Meer R, Anderson PD, Franco-Coronel OE, Kushner MH, Everett JH, Hameed O, Keeton EK, Ahdesmaki M, Grosskurth SE, Huszar D, Abdulkadir SA
J Natl Cancer Inst. 2015 107 (2)

PMID: 25505253 · PMCID: PMC4326311 · DOI:10.1093/jnci/dju407

BACKGROUND - PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence.

METHODS - A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ(2) test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided.

RESULTS - AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 ± 39% (P < .001), decreased cellular proliferation by 46 ± 14% (P = .016), and increased apoptosis by 326 ± 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients.

CONCLUSIONS - PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.

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MeSH Terms (22)

Administration, Oral Allografts Animals Antineoplastic Agents Apoptosis Biphenyl Compounds Cell Hypoxia Cell Proliferation Down-Regulation Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genes, myc Humans Male Mice Prostatic Neoplasms Prostatic Neoplasms, Castration-Resistant Protein Kinase Inhibitors Proto-Oncogene Proteins c-pim-1 Thiazolidines Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays

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