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

Histone deacetylase (HDAC) is closely related to the initiation and development of breast cancer (BC). Its inhibitor (HDACi) has been used to treat BC, while the efficacy of clinical trials was not reached expectations. HDACi combined with other drugs may be an effective strategy. This study explored the effect of HDACi tucidinostat combined with selinexor, an exportin 1 (XPO1) inhibitor, on ER+Her2- BC cell lines of MCF-7 (wt-TP53), MDA-MB-175 (wt-TP53), MDA-MB-134 (mut-TP53) and T47D (mut-TP53) in vitro and cell derived xenografts (CDX) of MCF-7 in nude mice in vivo. Results showed that both tucidinostat and selinexor showed better inhibitory activities on wt-TP53 BC (MCF-7 and MDA-MB-175) comparing with mut-TP53 BC (MDA-MB-134 and T47D). Tucidinostat combined with selinexor significantly improved the effects of tucidinostat alone on the proliferation and invasion inhibitions and apoptosis promotions of MCF-7 and MDA-MB-175 cells in vitro. It also significantly enhanced the effects of tucidinostat on up-regulating the expression levels of acetyl-p53, nuclear p53, total p53, p21, Bax and Cleaved Caspase-3, and down-regulating the expression levels of Cyclin D1 and Bcl-2 in MCF-7 or MDA-MB-175 cells. Results consistent with in vitro were also obtained in CDX of MCF-7 in vivo. Taken together, we believe that tucidinostat and selinexor are potentially effective drug combinations for the treatment of wt-TP53 BC, and the molecular mechanism may be through enhancing the activity of p53 in the nucleus of BC cells to suppress proliferation and invasion and promote apoptosis.