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

Austin N. Kirschner, Jie Wang, Riet Van Der Meer, Philip D. Anderson, Omar E. Franco-Coronel, Max H. Kushner, Joel H. Everett, Omar Hameed, Erika K. Keeton, Miika Ahdesmaki, Shaun E. Grosskurth, Dennis Huszar, Sarki A. Abdulkadir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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 χ2 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.

Original languageEnglish (US)
Article numberdju407
JournalJournal of the National Cancer Institute
Volume107
Issue number2
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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