Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
Abstract
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 01, 2021
- Source ID
- 10.1158/1535-7163.mct-21-0370
Entities
People
- Anil K. Sood
- Clifford Stephan
- Cristian Rodriguez-Aguayo
- Cristina Ivan
- Deanna Glassman
- Elaine Stur
- Emine Bayraktar
- Katelyn F. Handley
- Mark Kim
- Mary Sobieski
- Nghi Nguyen
- Paola Amero
- Prahlad T. Ram
- Reid T Powell
- Robert L Coleman
- Robiya Joseph
- Santosh K. Dasari
- Shannon N. Westin
- Shaolin Ma
- Sujanitha Umamaheswaran
- Yosef Landesman
- Yunfei Wen
Organizations
- American Cancer Society
- National Cancer Institute
- National Comprehensive Cancer Network
- National Institutes of Health
- Ovarian Cancer Research Alliance
- Texas A&M University
- United States Department of Defense
- University of South Florida
- University of Texas at Austin