Abstract 1061: Exportin 1 (XPO1) inhibition alone or in combination as a novel therapeutic strategy in osteosarcoma
Authors: Graves Laurie , Rupprecht Gabrielle , Altunel Erdem , Flamant Etienne M. , Rao Sneha , Sivara Dharshan , Lazarides Alexander L. , Hoskinson Sarah M. , Sheth Maya U. , Cheng Serene , Kim So Young , Ware Kathryn E. , Agarwal Anika , Cullen Mark M. , Syal Casey , Selmic Laura E. , Everitt Jeffrey I. , McCall Shannon J. , Eward Cindy , Kashyap Trinayan , Maloof Marie , Walker Christopher J. , Landesman Yosef , Wagner Lars , Eward William C. , Hsu David S. , Somarelli Jason A. 
Published: June 2022

Background: Osteosarcoma is an aggressive bone cancer in which therapeutic advancements have been limited over the last 30 years, in part due to genomic heterogeneity. The combination of high-throughput drug screening platforms that efficiently pinpoint drug sensitivities with patient-derived cross-species models is an innovative approach to address the critical need to identify novel treatment strategies for osteosarcoma patients.

Methods: We performed high-throughput drug screens on patient-derived osteosarcoma cell lines D418 (canine) and 17-3x (human), followed by validation of the top compounds, to identify drug sensitivities and novel therapeutic combinations.

Results: High-throughput drug screens using 2100 bioactive compounds show that osteosarcoma cell lines D418 and 17-3x exhibited sensitivity to standard-of-care chemotherapy drugs, inhibitors of XPO1 nuclear export, and proteasome inhibitors. The XPO1 inhibitor, verdinexor (VER), and the proteasome inhibitor, bortezomib (BORT), induced dose-dependent cytotoxicity in multiple osteosarcoma cell lines (D418, IC50VER: 3187 nM, IC50BORT: 2.8 nM; 17-3x IC50VER: 679 nM, IC50BORT: 10.9 nM). In addition, dual XPO1 and proteasome inhibition synergistically reduced cell proliferation in D418 (synergy score=12.89) and 17-3x (synergy score=17.87) cell lines (p &lt;0.05). Selinexor (SEL), an FDA approved XPO1 inhibitor used in combination with bortezomib to treat multiple myeloma, also demonstrated dose-dependent single-agent activity in patient-derived osteosarcoma cell lines (D418, IC50SEL: 370 nM; 17-3x IC50SEL: 101 nM). With drug screening of 119 oncology compounds in combination with selinexor in 17-3x cells, XPO1 inhibition again shows synergistic activity with proteasome inhibition in osteosarcoma.

Conclusions: Inhibition of XPO1-mediated nuclear export is a promising therapeutic strategy in osteosarcoma. These effects may be further potentiated when used in combination with other agents, such as proteasome inhibitors. Additional drug screening and validation assays are underway to identify novel synergistic agents for use in combination with XPO1 inhibitors in osteosarcoma.

Citation Format: Laurie Graves, Gabrielle Rupprecht, Erdem Altunel, Etienne M. Flamant, Sneha Rao, Dharshan Sivara, Alexander L. Lazarides, Sarah M. Hoskinson, Maya U. Sheth, Serene Cheng, So Young Kim, Kathryn E. Ware, Anika Agarwal, Mark M. Cullen, Casey Syal, Laura E. Selmic, Jeffrey I. Everitt, Shannon J. McCall, Cindy Eward, Trinayan Kashyap, Marie Maloof, Christopher J. Walker, Yosef Landesman, Lars Wagner, William C. Eward, David S. Hsu, Jason A. Somarelli. Exportin 1 (XPO1) inhibition alone or in combination as a novel therapeutic strategy in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1061.