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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jul 2

PMID 34206543

Citations 3

Authors

Md Hafiz Uddin

Yiwei Li

Husain Yar Khan

Irfana Muqbil

Amro Aboukameel

Rachel E Sexton

Shriya Reddy

Yosef Landesman

Trinayan Kashyap

Asfar S Azmi

Elisabeth I Heath

Affiliations

Soon will be listed here.

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 , and . Mechanistically, KPT-8602-PARPi suppressed , , and AR targets and . 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 , , , , , , , and . Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.

Citing Articles

CRM1 regulates androgen receptor stability and impacts DNA repair pathways in prostate cancer, independent of the androgen receptor.

Kumar R, Mendonca J, Shetty A, Yang Y, Owoyemi O, Wilson L FASEB J. 2025; 39(2):e70342.

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Role of Sam68 in different types of cancer (Review).

Jimenez-Cortegana C, Sanchez-Jimenez F, de la Cruz-Merino L, Sanchez-Margalet V Int J Mol Med. 2024; 55(1).

PMID: 39450529 PMC: 11537268. DOI: 10.3892/ijmm.2024.5444.

The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials.

Lai C, Xu L, Dai S Clin Transl Med. 2024; 14(5):e1684.

PMID: 38783482 PMC: 11116501. DOI: 10.1002/ctm2.1684.

Therapeutic Targeting of Exportin-1 in Childhood Cancer.

Galinski B, Alexander T, Mitchell D, Chatwin H, Awah C, Green A Cancers (Basel). 2021; 13(24).

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