Investigating Inhibition Of Nuclear Export In Breast Cancer Cells.

Abstract XPO1 (Exportin aka CRM1) is a mediator of nuclear export that is known to be dysregulated in cancers. Selective inhibitors of nuclear export (SINEs) have shown some promise in cancer treatment, but the mechanism is poorly understood in cancer specific subtypes. Here, we investigated XPO1 inhibition in breast cancer by treating a panel of breast cancer cell lines with a SINE (Selinexor) and saw a bimodal response, with most triple-negative cell lines showing sensitivity and some ER+ cell lines showing resistance to the therapy. Changes in the expression of BIRC5 (Survivin) have been previously implicated in XPO1 inhibitor response. Using RT-qPCR experiments we were able to show that after 24 hours of selinexor treatment, the expression of BIRC5 does change in two sensitive cell lines MDA-MB-231 and MCF7, but is not necessarily changed at earlier time points. To more holistically explore the mechanism of XPO1 inhibition induced cell death, we performed RNA-Seq and differential gene expression analysis on these two cell lines at 2, 8, and 24 hours post treatment with Selinexor (compared to vehicle). Our results indicate that several breast cancer and cell cycle associated genes show expression changes as early as 2 hours post-treatment and showed-consistent changes across the time-points. Overall, our analysis sheds light on the mechanism by which XPO1 inhibition induces cell death in breast cancer, which may help elucidate potential biomarkers as well as to nominate rationale combinations to explore with XPO1 inhibition. Citation Format: Robert F. Gruener, Geoffrey L. Greene, R. Stephanie Huang. Investigating inhibition of nuclear export in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 994.