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

Disclosures

J Natl Cancer Inst. 2015;107(2) 

In This Article

Abstract and Introduction

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.

Introduction

Prostate cancer afflicts one in six men during their lifetime. Up to 20% of low-risk and 40% of high-risk patients fail primary therapy with surgery and/or radiation, resulting in nearly 30000 deaths annually in the United States.[1] Patients who fail primary treatment and develop recurrence often have very limited treatment options. Given the high prevalence of prostate cancer and the high failure rate of current prostate cancer therapies, development of new therapies for aggressive prostate cancer is a high priority. The serine-threonine kinase PIM1 has emerged recently as a possible therapeutic target in prostate and other malignancies.[2] PIM1 phosphorylates several target substrates involved in inhibition of apoptosis and promotion of cell cycle progression, eg, BAD, CDC25A, p27KIP1, and the androgen receptor.[3,4] Notably, PIM1 dramatically cooperates with c-MYC to promote prostate cancer development in a kinase-dependent manner[5,6] and is required to maintain the tumorigenicity of these tumors.[7] These data highlight the potential of Pim1 as a therapeutic target in prostate cancer.[8]

AZD1208 is a novel pan-PIM kinase inhibitor that has shown efficacy in models of acute myeloid leukemia.[9–11] Here, we examined the efficacy of AZD1208 in treating MYC-driven prostate cancer.

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