Selinexor improves the anti-cancer effect of tucidinostat on TP53 wild-type breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Histone deacetylase inhibitors (HDACi) are investigated for breast cancer (BC) treatment, but clinical efficacy has been limited.
• Combination therapies involving HDAC inhibitors may offer improved therapeutic strategies for BC.
• Exportin 1 (XPO1) inhibitors represent a novel class of drugs with potential anti-cancer activity.

Purpose of the Study:

• To investigate the combined effects of tucidinostat (HDACi) and selinexor (XPO1 inhibitor) on ER+/Her2- BC cell lines.
• To evaluate the efficacy of this combination in vitro and in vivo using cell-derived xenografts (CDX).
• To explore the underlying molecular mechanisms, particularly the role of p53 activation.

Main Methods:

• In vitro studies using ER+/Her2- BC cell lines (MCF-7, MDA-MB-175, MDA-MB-134, T47D) with varying TP53 statuses.
• In vivo studies using MCF-7 CDX models in nude mice.
• Analysis of cell proliferation, invasion, apoptosis, and expression of key proteins (p53, p21, Cyclin D1, Bcl-2, Bax, Cleaved Caspase-3).

Main Results:

• Both tucidinostat and selinexor demonstrated greater inhibitory activity against wild-type TP53 BC cells compared to mutant TP53 cells.
• The combination of tucidinostat and selinexor significantly enhanced anti-proliferative, anti-invasive, and pro-apoptotic effects in vitro.
• In vivo studies in CDX models corroborated the in vitro findings, showing enhanced therapeutic efficacy.

Conclusions:

• Tucidinostat combined with selinexor is a potentially effective therapeutic strategy for wild-type TP53 ER+/Her2- breast cancer.
• The combination therapy enhances the activity of p53 in the nucleus of BC cells, suppressing proliferation and invasion while promoting apoptosis.
• This combination warrants further clinical investigation for the treatment of specific breast cancer subtypes.