[VIRTUAL] Nuclear export inhibitor KPT-8602 synergize with PARP inhibitors in castration resistant metastatic prostate cancer (AACR 2021)
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...Interestingly, KPT-8602 with or without the PARPi olaparib was shown to reduce homologous recombination (HR) regulated DNA damage response (DDR) targets including BRCA1, BRCA2, BLM, XRCC3, EXO1, RMI1, RMI2, RAD54L, CHEK1, LIG1 and RAD51 (P < 0.01).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.