Nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer

Narmeen Rashid

Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic breast cancer subtype. Chemotherapy is standard of care for TNBC patients, but many patients develop acquired chemoresistance. It is necessary to identify targeted therapies for chemo-resistant, advanced TNBC. We used high throughput drug screening to identify promising drug candidates. Combinatorial assays were performed on the drugs of interest to identify synergistically cytotoxic drug pairs. We identified two targeted drug pairs, both including a selective inhibitor of nuclear export (SINE). These drug pairs were then tested in vivo. We found that the combination of a XPO1 inhibitor (SINE) and a dual mTOR/PI3K inhibitor demonstrated significant anti-tumor activity. Single-cell RNA sequencing and immunohistochemistry revealed that the drug targets were abundantly expressed in TNBC samples. Additionally, analysis of a 855-patient dataset revealed that XPO1 overexpression was negatively associated with metastasis free survival. Nuclear export inhibitor-based therapies warrant further preclinical exploration in TNBC.




Chuck Harrell