PARP and CDK4/6 inhibitor combination therapy induces apoptosis and suppresses neuroendocrine differentiation in prostate cancer

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 (Ola) and palbociblib (Palbo) or abemaciclib (Abema) treatment resulted in synergistic suppression of the p-Rb1-E2F1 signaling axis at the transcriptional and post-translational 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-2), CDK1, and neuroendocrine differentiation (NED) markers in vitro and in vivo. In addition, Ola+Palbo or Ola+Abema 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.

Related Products

Cat.No. Product Name Information
S1060 Olaparib (AZD2281) Olaparib (AZD2281, KU0059436) is a selective inhibitor of PARP1/2 with IC50 of 5 nM/1 nM in cell-free assays, 300-times less effective against tankyrase-1. Olaparib induces significant autophagy that is associated with mitophagy in cells with BRCA mutations.

Related Targets

PARP Mitophagy Autophagy