IKKε Inhibitor Amlexanox Promotes Olaparib Sensitivity through the C/EBP-β-Mediated Transcription of Rad51 in Castrate-Resistant Prostate Cancer.

Abstract

Simple SummaryMost men with advanced hormone-sensitive prostate cancer (HSPC) treated with androgen deprivation therapy will develop castrate resistant prostate cancer (CRPC), a lethal form of prostate cancer (PC). Our group has previously shown that IKKε expression is stronger in CRPC tumors and correlates with aggressive PC. Moreover, we have shown that IKKε depletion or inhibition (BX795, Amlexanox) decrease CRPC cell proliferation and tumor volume in an in vivo mouse model. We also demonstrate that IKKε inhibitors specifically target CRPC to induce a senescent phenotype as well as DNA damage and genomic instability. In this study, we demonstrated that IKKε depletion or inhibition block C/EBP-β recruitment on Rad51 promoter to decrease promoter activity. We have also shown that Amlexanox treatment sensitizes CRPC cells to Olaparib in vitro and in mouse models. Taken together, targeting IKKε with Amlexanox combined with Olaparib may lead to additional effective therapeutic strategies in the management of patients with CRPC.The progression of prostate cancer (PC) is often characterized by the development of castrate-resistant PC (CRPC). Patients with CRPC are treated with a variety of agents including new generation hormonal therapies or chemotherapy. However, as the cancer develops more resistance mechanisms, these drugs eventually become less effective and finding new therapeutic approaches is critical to improving patient outcomes. Previously, we have shown that IKKε depletion and IKKε inhibitors, BX795 and Amlexanox, decrease CRPC cell proliferation in vitro and in vivo and that IKKε inhibitors induce a senescence phenotype accompanied by increased DNA damage and genomic instability in CRPC cells. Here, we describe a new role for IKKε in DNA damage repair involving Rad51 and examine the therapeutic potential of Amlexanox combined with the PARP inhibitor Olaparib in CRPC cell lines. Combining Amlexanox with Olaparib decreased CRPC cell proliferation and enhanced DNA damage through the inhibition of Olaparib-induced Rad51 recruitment and expression in CRPC cells or IKKε-depleted PC-3 cells. We demonstrated that Rad51 promoter activity, measured by luciferase assay, was decreased with Amlexanox treatment or IKKε depletion and that Amlexanox treatment decreased the occupancy of transcription factor C/EBP-β on the Rad51 promoter. Our mouse model also showed that Amlexanox combined with Olaparib inhibited tumor growth of CRPC xenografts. Our study highlights a new role for IKKε in DNA damage repair through the regulation of Rad51 transcription and provides a rationale for the combination of Amlexanox and Olaparib in the treatment of patients with CRPC.