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

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.

LAMC2 as a therapeutic target for cancers.

Cancer is the leading cause of morbidity and mortality in developed countries and the second major cause of death in developing countries. Laminins are crucial proteins in the basal lamina (one of the layers of the basement membrane), and these form a protein network that influences both normal and transformed cell differentiation, migration and adhesion, as well as phenotype and survival. The basement membranes act as a mechanical barrier to tumor growth, but these molecules, including laminins, are also important autocrine factors produced by cancers to promote tumorigenesis. Several studies in cancers have shown the importance of LAMC2, a laminin component. The elevated expression of LAMC2 on cancer cells appears to drive tumorigenesis through its interactions with several cell-surface receptors including α6ß4 and α3ß1 integrins and EGFRs. The accumulating evidence indicates that LAMC2-mediated signaling network plays an important role in the progression, migration and invasion of multiple types of cancer, suggesting that it might be a potential therapeutic anticancer target for inhibiting tumorigenesis. Furthermore, elevated serum levels of LAMC2 in cancer patients might be an attractive serum-based diagnostic biomarker.