Abstract 569: Rational combination approaches with CRM-1 inhibitor in ovarian cancer

Abstract

Abstract Background: After the frontline treatment, the majority of patients diagnosed with ovarian cancer at an advanced stage will develop recurrence (80%); thus, there is an urgent need for novel therapeutic approaches. Purpose: Selinexor is a CRM1 inhibitor, which is a selective inhibitor of nuclear export and has demonstrated antitumor effects in ovarian cancer. Here, we examined the efficacy of selinexor alone and in combination with PARP inhibitors in ovarian cancer. As Selinexor reduces the expression of DNA damage repair proteins, we hypothesized that this combination should reduce the number of DNA damage repair proteins, resulting in synergistic tumor cell death. Methods: Western blot was performed to assess baseline CRM1 expression in eleven ovarian cancer cell lines. We tested the efficacy of selinexor alone and in combination with olaparib in ovarian cancer cells (A2780ip2, OVCAR5). Combination Indices (CI) were calculated with CompuSyn and were considered synergistic when CI less than 1 for classic MTT arrays. We used the annexin V-FITC/PI assay to assess apoptosis as a result of selinexor and olaparib alone or in combination. Results: Baseline CRM1 expression was positive in eight of eleven ovarian cancer cell lines tested. The average IC50 in A2780ip2 for selinexor and olaparib was 0.09uM and 0.97uM, respectively. The median combination index was 0.81 in A2780ip2 and 0.92 in OVCAR5 cells. Flow cytometry demonstrated an additive effect of selinexor and olaparib in A2780ip2 cell apoptosis (7.34% and 7.93%, respectively, v. 17.86%). Conclusions: Selinexor demonstrates synergistic activity with olaparib, and this combination warrants further investigation. Citation Format: Katelyn F. Handley, Cristian Rodriguez-Aguayo, Shaolin Ma, Mark S. Kim, Prahlad T. Ram, Anil K. Sood. Rational combination approaches with CRM-1 inhibitor in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 569.