TY - JOUR
T1 - PARP and CDK4/6 inhibitor combination therapy induces apoptosis and suppresses neuroendocrine differentiation in prostate cancer
AU - Wu, Cheng
AU - Peng, Shan
AU - Pilie, Patrick G.
AU - Geng, Chuandong
AU - Park, Sanghee
AU - Manyam, Ganiraju C.
AU - Lu, Yungang
AU - Yang, Guang
AU - Tang, Zhe
AU - Kondraganti, Shakuntala
AU - Wang, Daoqi
AU - Hudgens, Courtney W.
AU - Ledesma, Debora A.
AU - Marques-Piubelli, Mario L.
AU - Torres-Cabala, Carlos A.
AU - Curry, Jonathan L.
AU - Troncoso, Patricia
AU - Corn, Paul G.
AU - Broom, Bradley M.
AU - Thompson, Timothy C.
N1 - Funding Information:
P.G. Piliéreports grants from Prostate Cancer Foundation and grants from ASCO Career Development Award outside the submitted work. T.C. Thompson reports grants from the NCI during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
We acknowledge the editorial assistance of Sarah E. Townsend. This research was supported by MD Anderson NCI Prostate Cancer SPORE Grant P50 CA140388 and NCI Cancer Center Support Grant P30 CA16672.
Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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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U2 - 10.1158/1535-7163.MCT-20-0848
DO - 10.1158/1535-7163.MCT-20-0848
M3 - Article
C2 - 34158347
AN - SCOPUS:85109257735
SN - 1535-7163
VL - 20
SP - 1680
EP - 1691
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -