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

Hélène Marijon; Sigal Gery; Hua Chang; Yosef Landesman; Sharon Shacham; Dhong Hyun Lee; Aimery de Gramont; Harold Phillip Koeffler

doi:10.18632/oncotarget.28047

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

Oncotarget. 2021 Aug 31;12(18):1749-1762. doi: 10.18632/oncotarget.28047.

Authors

Hélène Marijon^{1

2}, Sigal Gery¹, Hua Chang³, Yosef Landesman³, Sharon Shacham³, Dhong Hyun Lee¹, Aimery de Gramont^{2

4}, Harold Phillip Koeffler^{1

5}

Affiliations

¹ Cedars-Sinai Medical Center, Division of Hematology/Oncology, University of California, Los Angeles, CA 90048, USA.
² Department of Medical Oncology, Franco-British Hospital (Fondation Cognacq-Jay), Levallois-Perret, France.
³ Karyopharm Therapeutics Inc., Newton, MA 02459, USA.
⁴ Statistical Unit, Aide et Recherche en Cancérologie Digestive Foundation, Levallois-Perret, France.
⁵ Cancer Science Institute of Singapore, National University of Singapore 117599, Singapore.

Abstract

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 BRCA mutations. We examined the effects of co-treatment with selinexor and olaparib in TNBC cell lines. BRCA1 wildtype (BRCA1-wt) and BRCA1 mutant (BRCA1-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 BRCA1-wt and BRCA1-mut TNBC cell lines. Treatment with selinexor inhibited cell proliferation and survival of all TNBC cell lines tested in vitro. 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 (BRCA1-wt) and MDA-MB-436-derived (BRCA1-mut) xenografts. As co-treatment with selinexor and olaparib exhibits anti-tumor activity regardless of BRCA1 mutation status, the clinical implications of the combination warrant further investigation.

Keywords: BRCA1; XPO1; olaparib; selinexor; triple negative breast cancer.