PIM Kinase Inhibitor AZD1208 for Treatment of MYC-Driven Prostate Cancer
PIM Kinase Inhibitor AZD1208 for Treatment of MYC-Driven Prostate Cancer
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DOI：
10.1093/jnci/dju407
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发表时间：
2015-02-01
影响因子：
10.3
通讯作者：
Abdulkadir, Sarki A.
中科院分区：
文献类型：
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作者：
Kirschner, Austin N.;Wang, Jie;Abdulkadir, Sarki A.
背景：PIM 1激酶与c-MYC在人前列腺癌（PC）中共表达，并显著增强c-MYC诱导的致瘤性。在这里，我们研究了一种新的口服PIM抑制剂AZD 1208对前列腺肿瘤发生和复发的影响。方法：用AZD 1208治疗小鼠c-MYC/Pim 1转导的组织重组PC模型、Myc-CaP同种异体移植物和人PC异种移植物（每组n = 5-11）。研究了雄激素敏感性和去势抵抗性前列腺癌（CRPC）模型以及缺氧和辐射的影响。RNA测序用于分析药物诱导的基因表达变化。结果采用卡方检验。学生t检验和非参数Mann-Whitney秩和U检验。结果：AZD 1208在组织重组体、Myc-CaP和人PC异种移植模型中抑制肿瘤发生。PIM抑制使c-MYC/Pim 1移植物生长降低54.3 +/- 39%（P < .001），细胞增殖降低46 +/- 14%（P =.016），细胞凋亡增加326 +/- 170%（P =.039）。AZD 1208抑制多种促肿瘤发生途径，包括MYC基因程序。然而，它也下调了p53通路。缺氧和辐射诱导前列腺癌细胞中的PIM 1，AZD 1208起辐射增敏剂的作用。去势后复发的肿瘤对AZD 1208或放射治疗有一过性反应，联合治疗对肿瘤生长的抑制作用更持久。从复发的AZD 1208耐药肿瘤建立的细胞系再次显示p53通路的下调。辐照AZD 1208治疗的肿瘤强烈上调p53，为联合治疗的有效性提供了可能的机制解释。最后，AZD 1208耐药基因签名被发现与PC patient.Conclusions生化复发相关：PIM抑制是一种潜在的治疗MYC驱动的前列腺癌，包括CRPC，其有效性可能会增强激活剂的p53通路，如辐射。
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 chi(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.