High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models
High Efficacy of Combination Therapy Using PI3K/AKT Inhibitors with Androgen Deprivation in Prostate Cancer Preclinical Models
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DOI：
10.1016/j.eururo.2014.08.053
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发表时间：
2015-06-01
期刊：
影响因子：
23.4
通讯作者：
van Weerden, Wytske M.
中科院分区：
文献类型：
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作者：
Marques, Rute B.;Aghai, Ashraf;van Weerden, Wytske M.
背景：磷脂酰肌醇-4,5-二磷酸3激酶(PI3K)/AKT通路在前列腺癌（PCa）进展过程中经常通过磷酸酶和紧张素同源物（PTEN）基因的丢失或突变而激活。继雄激素受体（AR）途径之后，它是前列腺癌生长的第二个主要驱动因素。目的：评估新型PI3K/ akt靶向治疗在PCa模型中的疗效，无论是单药还是联合雄激素剥夺。设计、环境和参与者：我们在体外测试了12株人PCa细胞系对AKT抑制剂AZD5363和PI3K β / δ抑制剂AZD8186的敏感性。AZD5363和AZD8186联合去势在pten阴性和pten阳性患者来源的异种移植物体内进行了评估。收集肿瘤和血浆进行生物标志物分析。结果测量和统计分析：体外生长抑制测定采用甲基噻唑基二苯基溴化四氮唑测定法。体内疗效通过卡尺测量皮下肿瘤体积来监测。采用Western blot、酶联免疫吸附法和实时聚合酶链反应分析PI3K/AKT和AR通路活性。结果和局限性：AZD5363和AZD8186分别抑制12株PCa细胞系中的10株和7株的体外生长，且在雄激素消耗下敏感性增加。在体内，与安慰剂相比，AZD5363和azd8186作为单一药物对pten阴性PC346C异种移植物生长的抑制作用分别为60%和66%。重要的是，任何一种药物与去势的联合使用都导致了长期的肿瘤消退，并在治疗停止后持续存在。ar靶基因klikrein相关肽酶3 （KLK3，也称PSA）的表达；跨膜蛋白酶丝氨酸2 (TMPRSS2)；PI3K/AKT抑制后，FK506结合蛋白5 （FKBP5）上调。在pten阳性的PC310模型中，两种化合物均未抑制肿瘤生长。结论：在pten阴性PCa模型中，联合激素治疗可提高PI3K/ akt靶向药物的疗效。ar靶基因对PI3K/AKT抑制的上调表明PI3K- ar通路之间存在代偿性串扰。这些数据强烈支持进一步的临床评估。患者总结：PTEN基因失活是促进前列腺癌（PCa）进展的常见事件。这项临床前研究表明，新型pten靶向药物在PCa模型上具有强大的抗癌活性，特别是与激素治疗联合使用时。(C) 2014欧洲泌尿外科协会。Elsevier B.V.版权所有。
Background: The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway is frequently activated during prostate cancer (PCa) progression through loss or mutation of the phosphatase and tensin homolog (PTEN) gene. Following the androgen receptor (AR) pathway, it is the second major driver of PCa growth.Objective: To assess efficacy of novel PI3K/AKT-targeted therapies in PCa models, as a single agent and in combination with androgen deprivation.Design, setting, and participants: Twelve human PCa cell lines were tested in vitro for sensitivity to the AKT inhibitor AZD5363 and the PI3K beta/delta inhibitor AZD8186. The combination of AZD5363 and AZD8186 with castration was evaluated in vivo in PTEN-negative versus PTEN-positive patient-derived xenografts. Tumors and plasma were collected for biomarker analysis.Outcome measurements and statistical analysis: In vitro growth inhibition was determined by methylthiazolyldiphenyl-tetrazolium bromide assay. In vivo efficacy was monitored by caliper measurements of subcutaneous tumor volume. PI3K/AKT and AR pathway activity was analyzed by Western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction.Results and limitations: AZD5363 and AZD8186 inhibited in vitro growth of 10 of 12 and 7 of 12 PCa cell lines, respectively, with increased sensitivity under androgen depletion. In vivo, AZD5363 andAZD8186 as single agents significantly inhibited growth of PTEN-negative PC346C xenografts compared to placebo by 60% and 66%, respectively. Importantly, combination of either agent with castration resulted in long-lasting tumor regression, which persisted after treatment cessation. Expression of AR-target genes kallikrein-related peptidase 3 (KLK3, also known as PSA); transmembrane protease, serine 2 (TMPRSS2); and FK506 binding protein 5 (FKBP5) was upregulated after PI3K/AKT inhibition. Neither compound inhibited tumor growth in the PTEN-positive PC310 model.Conclusions: Combination with hormonal therapy improved efficacy of PI3K/AKT-targeted agents in PTEN-negative PCa models. Upregulation of AR-target genes upon PI3K/AKT inhibition suggests a compensatory crosstalk between the PI3K-AR pathways. These data strongly advocate for further clinical evaluation.Patient summary: Inactivation of the PTEN gene is a common event promoting prostate cancer (PCa) progression. This preclinical study illustrates the potent anticancer activity of novel PTEN-targeted drugs on PCa models, particularly in combination with hormonal therapy. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.