Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status

• Published in: Oncotarget 2021-08, Vol.12 (18), p.1749-1762
• Main Authors: Marijon, Hélène, Gery, Sigal, Chang, Hua, Landesman, Yosef, Shacham, Sharon, Lee, Dhong Hyun, de Gramont, Aimery, Koeffler, Harold Phillip
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.28047

Triple negative breast cancer (TNBC) is a deadly disease with limited treatment options. Selinexor is a selective inhibitor of nuclear export that binds covalently to exportin 1 thereby reactivating tumor suppressor proteins and downregulating expression of oncogenes and DNA damage repair (DDR) proteins. Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor approved for the treatment of patients with breast cancer harboring mutations. We examined the effects of co-treatment with selinexor and olaparib in TNBC cell lines. wildtype ( -wt) and mutant ( -mut) TNBC cell lines were treated with selinexor and/or olaparib and effects on cell viability and cell cycle were evaluated. The effects of treatment were also evaluated in mouse xenograft models generated with -wt and -mut TNBC cell lines. Treatment with selinexor inhibited cell proliferation and survival of all TNBC cell lines tested . This effect was enhanced following treatment of the cells with the combination of selinexor and olaparib, which showed synergistic effects on tumor growth inhibition in MDA-MB-468-derived ( -wt) and MDA-MB-436-derived ( -mut) xenografts. As co-treatment with selinexor and olaparib exhibits anti-tumor activity regardless of mutation status, the clinical implications of the combination warrant further investigation.