D'Abronzo L S, Bose S, Crapuchettes M E, Beggs R E, Vinall R L, Tepper C G, Siddiqui S, Mudryj M, Melgoza F U, Durbin-Johnson B P, deVere White R W, Ghosh P M
VA Northern California Health Care System, University of California at Davis, Sacramento, CA, USA.
Department of Urology, University of California Davis School of Medicine, University of California at Davis, Sacramento, CA, USA.
Oncogene. 2017 Nov 16;36(46):6359-6373. doi: 10.1038/onc.2017.233. Epub 2017 Jul 24.
The antiandrogen bicalutamide is widely used in the treatment of advanced prostate cancer (PCa) in many countries, but its effect on castration-resistant PCa (CRPC) is limited. We previously showed that resistance to bicalutamide results from activation of mechanistic target of rapamycin (mTOR). Interestingly, clinical trials testing combinations of the mTOR inhibitor RAD001 with bicalutamide were effective in bicalutamide-naïve CRPC patients, but not in bicalutamide-pretreated ones. Here we investigate causes for their difference in response. Evaluation of CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E(S209) phosphorylation is associated with resistance to the combination. We confirmed using a human-derived tumor xenograft mouse model that bicalutamide pre-treatment is associated with an increase in eIF4E(S209) phosphorylation. Thus, AR suppressed eukaryotic initiation factor 4E (eIF4E) phosphorylation, while the use of antiandrogens relieved this suppression, thereby triggering its increase. Additional investigation in human prostatectomy samples showed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67. Small interfering RNA-mediated knockdown (k/d) of eIF4E-sensitized CRPC cells to RAD001+bicalutamide, whereas eIF4E overexpression induced resistance. Inhibition of eIF4E phosphorylation by treatment with CGP57380 (an inhibitor of mitogen-activated protein kinase-interacting serine-threonine kinases MAP kinase-interacting kinase 1 (Mnk1/2), the eIF4E upstream kinase) or inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2), the upstream kinase-regulating Mnk1/2, also sensitized CRPC cells to RAD001+bicalutamide. Examination of downstream targets of eIF4E-mediated translation, including survivin, demonstrated that eIF4E(S209) phosphorylation increased cap-independent translation, whereas its inhibition restored cap-dependent translation, which could be inhibited by mTOR inhibitors. Thus, our results demonstrate that while combinations of AR and mTOR inhibitors were effective in suppressing tumor growth by inhibiting both AR-induced transcription and mTOR-induced cap-dependent translation, pre-treatment with AR antagonists including bicalutamide increased eIF4E phosphorylation that induced resistance to combinations of AR and mTOR inhibitors by inducing cap-independent translation. We conclude that this resistance can be overcome by inhibiting eIF4E phosphorylation with Mnk1/2 or ERK1/2 inhibitors.
抗雄激素药物比卡鲁胺在许多国家被广泛用于治疗晚期前列腺癌（PCa），但其对去势抵抗性前列腺癌（CRPC）的疗效有限。我们之前表明，对比卡鲁胺的耐药性源于雷帕霉素机制性靶点（mTOR）的激活。有趣的是，测试mTOR抑制剂RAD001与比卡鲁胺联合使用的临床试验对未接受过比卡鲁胺治疗的CRPC患者有效，但对接受过比卡鲁胺预处理的患者无效。在此，我们研究它们反应差异的原因。对CRPC细胞系的评估确定了体外耐药与敏感模型，并揭示eIF4E（S209）磷酸化增加与对联合治疗的耐药性相关。我们使用人源肿瘤异种移植小鼠模型证实，比卡鲁胺预处理与eIF4E（S209）磷酸化增加有关。因此，雄激素受体（AR）抑制真核起始因子4E（eIF4E）的磷酸化，而使用抗雄激素药物可解除这种抑制，从而导致其增加。对人类前列腺切除样本的进一步研究表明，eIF4E磷酸化增加与细胞增殖标志物Ki67密切相关。小干扰RNA介导的eIF4E敲低使CRPC细胞对RAD001+比卡鲁胺敏感，而eIF4E过表达则诱导耐药性。用CGP57380（一种丝裂原活化蛋白激酶相互作用的丝氨酸 - 苏氨酸激酶即丝裂原活化蛋白激酶相互作用激酶1/2（Mnk1/2）的抑制剂，eIF4E的上游激酶）或细胞外信号调节激酶1/2（ERK1/2）的抑制剂（调节Mnk1/2的上游激酶）处理以抑制eIF4E磷酸化，也使CRPC细胞对RAD001+比卡鲁胺敏感。对eIF4E介导的翻译的下游靶点（包括生存素）的检测表明，eIF4E（S209）磷酸化增加了不依赖帽结构的翻译，而其抑制恢复了依赖帽结构的翻译，这可被mTOR抑制剂抑制。因此，我们的结果表明，虽然AR和mTOR抑制剂联合使用通过抑制AR诱导的转录和mTOR诱导的依赖帽结构的翻译有效抑制肿瘤生长，但包括比卡鲁胺在内的AR拮抗剂预处理会增加eIF4E磷酸化，通过诱导不依赖帽结构的翻译诱导对AR和mTOR抑制剂联合治疗的耐药性。我们得出结论，这种耐药性可以通过用Mnk1/2或ERK1/2抑制剂抑制eIF4E磷酸化来克服。
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