Abstract 1091: Nuclear export inhibitor KPT-8602 synergize with PARP inhibitors in castration resistant metastatic prostate cancer

Abstract

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization dependent inactivation of critical cellular proteins. Earlier we showed that over-expression of the nuclear export protein exportin 1 (XPO1) is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that the selective inhibitor of nuclear export (SINE) compound selinexor and the second generation SINE eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with three different PARP inhibitors (PARPi) namely olaparib, veliparib and rucaparib in a mCRPC model. Growth inhibition was determined by MTT assay. Drug synergy analysis was done and the isobolograms were generated from Calcusyn 2.1 software (Biosoft, Cambridge, UK). Other techniques include: colony formation assay, apoptosis determination by flow cytometry (annexin V-propidium iodide), real time RT-qPCR (SYBR green I), western blotting, immunofluorescence etc. For the determination of band density, NIH ImageJ 1.5Oi software was utilized. KPT-8602 synergized with all three studied PARPi (CI Taken together, this study revealed the therapeutic potential of a novel combination including second generation SINE compound KPT-8602 and PARP inhibitors for the growth inhibition of mCRPC cells. Pre-clinical xenograft studies testing the efficacy of SINE-PARPi as well as a phase II clinical study combining KPT-8602-PARPi is planned. Citation Format: Md. Hafiz Uddin, Yiwei Li, Amro Aboukameel, Husain Y. Khan, Vijendra Singh, Shriya Reddy, Suresh Kumar Balasubramanian, Yosef Landesman, Trinayan Kashyap, Elisabeth I. Heath, Asfar S. Azmi. Nuclear export inhibitor KPT-8602 synergize with PARP inhibitors in castration resistant metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1091.