Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells.

Md Hafiz Uddin,Shriya Reddy,Yiwei Li,Yosef Landesman,Asfar S Azmi,Elisabeth I Heath,Irfana Muqbil,Trinayan Kashyap,Amro Aboukameel,Rachel E Sexton,Husain Yar Khan

doi:10.3390/ijms22136676

Abstract

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation 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 PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes BAX, TP53 and CASPASE 9. Mechanistically, KPT-8602-PARPi suppressed AR, ARv7, PSA and AR targets FOXA1 and UBE2C. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.

Highlights

Metastatic prostate cancer is a lethal disease that remains the second leading cause of death among men in the United States [1]
The 22rv1 cells showed lower BRCA2 levels compared to non-metastatic castration-resistant prostate cancer (mCRPC) cell lines (Figure S1)
Isobologram analysis revealed that the combination of KPT-8602 and poly(ADP) ribose phosphate (PARP) inhibitors exerted a synergistic inhibitory effect on 22rv1 cells (Figure 1A–C; right panel), as the combination index (CI) values were below 1 (Figure 1A–C; middle panel)

Summary

Introduction

Metastatic prostate cancer (mPCa) is a lethal disease that remains the second leading cause of death among men in the United States [1]. For the past several decades Androgen deprivation therapy (ADT) has been considered as a primary treatment option for advanced symptomatic PCa [2]. Patients initially respond to ADT, most of them develop metastatic castration-resistant prostate cancer (mCRPC) [3]. Increasing evidence suggests that PCa and CRPC modulates androgen receptor (AR), Akt, Src, Wnt, hedgehog and other signal transduction pathways at the molecular level [4,5,6,7,8]. The AR signaling is considered as the most important one [4]

Methods

Results

Conclusion