PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer

奥拉帕尼 癌症研究 细胞周期蛋白依赖激酶1 前列腺癌 帕博西利布 LNCaP公司 E2F1 细胞周期 生物 癌症 聚ADP核糖聚合酶 医学 内科学 乳腺癌 基因 转移性乳腺癌 聚合酶 生物化学
作者
Cheng Wu,Shan Peng,Patrick G. Pilié,Chuandong Geng,Sanghee Park,Ganiraju C. Manyam,Yungang Lu,Guang Yang,Zhe Tang,Shakuntala Kondraganti,Daoqi Wang,Courtney W. Hudgens,Debora Alejandra Ledesma,Mario L. Marques‐Piubelli,Carlos A. Torres‐Cabala,Jonathan L. Curry,Patricia Troncoso,Paul G. Corn,Bradley M. Broom,Timothy C. Thompson
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:20 (9): 1680-1691 被引量:36
标识
DOI:10.1158/1535-7163.mct-20-0848
摘要

We analyzed the efficacy and mechanistic interactions of PARP inhibition (PARPi; olaparib) and CDK4/6 inhibition (CDK4/6i; palbociclib or abemaciclib) combination therapy in castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) models. We demonstrated that combined olaparib and palbociblib or abemaciclib treatment resulted in synergistic suppression of the p-Rb1-E2F1 signaling axis at the transcriptional and posttranslational levels, leading to disruption of cell-cycle progression and inhibition of E2F1 gene targets, including genes involved in DDR signaling/damage repair, antiapoptotic BCL-2 family members (BCL-2 and MCL-1), CDK1, and neuroendocrine differentiation (NED) markers in vitro and in vivo In addition, olaparib + palbociclib or olaparib + abemaciclib combination treatment resulted in significantly greater growth inhibition and apoptosis than either single agent alone. We further showed that PARPi and CDK4/6i combination treatment-induced CDK1 inhibition suppressed p-S70-BCL-2 and increased caspase cleavage, while CDK1 overexpression effectively prevented the downregulation of p-S70-BCL-2 and largely rescued the combination treatment-induced cytotoxicity. Our study defines a novel combination treatment strategy for CRPC and NEPC and demonstrates that combination PARPi and CDK4/6i synergistically promotes suppression of the p-Rb1-E2F1 axis and E2F1 target genes, including CDK1 and NED proteins, leading to growth inhibition and increased apoptosis in vitro and in vivo Taken together, our results provide a molecular rationale for PARPi and CDK4/6i combination therapy and reveal mechanism-based clinical trial opportunities for men with NEPC.
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