Abstract 1841: Selective inhibitors of nuclear export (SINE) activate multiple tumor suppressor pathways and kill prostate cancer cells across multiple genotypes in vitro and in vivo

Abstract

Abstract CRM1 (Xpo1) is a key nuclear export protein which controls the nuclear export of multiple tumor suppressor proteins (TSP) and cell proliferation pathways including p53, p21, FOXO, PI3K/AKT, Wnt/ß-catenin and NF-κB. Mislocalization of TSP can abrogate their functions as well as render chemotherapies ineffective. Induction of nuclear expression of TSP and chemotherapy targets, by CRM1 inhibition can restore their tumor suppressor functions and increase drug sensitivity. We have developed orally active, small molecule SINE that irreversibly and potently inhibit CRM1 mediated nuclear export of multiple TSP and other cargoes (IC50 < 100 nM). Here, we describe in vitro results using SINE compounds, KPT-185 in vitro and KPT-251 in vitro and in vivo on seven prostate cancer (PrCa) cell lines representing distinct differentiation/progression states of disease and genotypes: LAPC-4 (Androgen receptor [AR] positive, androgen dependent with low Akt/mTOR activities, p53 wt); LnCaP (AR positive, androgen dependent with high Akt/mTOR activities, p53 wt); LnCaP-C81 and LnCaP-C4-2B (AR positive, androgen independent with high Akt/mTOR activities, p53 wt); 22rv1 (AR positive, androgen independent with low Akt/mTOR activities, p53 wt); PC3 (AR negative, with high Akt/mTOR activites and no p53 function (p53 del) and DU145 (AR negative, with low Akt/mTOR activites and mutant p53). Benign prostatic hyperplasia line (BPH1) and Prostatic epithelial line (EPN) were used as non-neoplastic controls. We show that SINE block CRM1 mediated nuclear export of FOXO and p53 with a IC50 values <100 nM in both PrCa and non-neoplastic cell lines. KPT compounds are selectively cytotoxic to PrCa lines with EC50s between 10 and 1000 nM, and show limited cytotoxicity on the non-neoplastic EPN and BPH1 lines (EC50 >5-20 μM). SINE cytotoxic effects are independent of p53 status, and induce caspase-3 activation. SINE display synergistic effects in combination with cisplatin and docetaxel in vitro with combination indices between 0.3 and 0.8. In vivo results indicate that KPT-251 show a dose-dependent inhibition of tumor growth. KPT251 was also synergistic when administered at 30mg/kg/5 days/week per os with docetaxel and cisplatin by using the aggressive p53 wt 22rv1 xenografts. Taken together, CRM1 inhibition represents a completely novel, neoplasia-selective and well- tolerated target for use as single agent or in combination with chemotherapy for PrCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1841. doi:1538-7445.AM2012-1841