Date of Award

2023

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

John Wurpel

Second Advisor

Zhe-Sheng Chen

Third Advisor

Sandra Reznik

Abstract

Cancer remains a growing public health challenge worldwide. Although the development of chemotherapies has effectively reduced the cancer death rate and improved patients’ prognosis, the frequent occurrence of multi-drug resistance (MDR) in cancer has caused impairments on the efficacy of many structure-unrelated anticancer agents, leading to treatment failure and recurrence. One of the most common causes of MDR is the overexpression of ATP-binding cassette (ABC) transporters on cancer cell membranes, which transport anticancer drugs out of cancer cells, thereby reducing the intracellular drug concentration. BMN-673 (talazoparib) is a potent poly (ADP-ribose) polymerase (PARP) inhibitor that is approved for BRCA-mutated HER2-negative locally advanced or metastatic breast cancer and is under clinical investigations for treating other solid tumors. The present study aims to explore the role of ABCC1 and ABCG2 transporters in regulating the efficacy of BMN-673 in ovarian cancer. The cell viability tests indicated that the effect of BMN-673 is limited in both drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2. The known ABCC1 inhibitor, ONO-1078, and ABCG2 inhibitor, cabozantinib, can sensitize ABCC1- or ABCG2-overexpressing cells to BMN-673. The computational molecular docking analysis suggested that BMN-673 interacts with the drug-binding pocket of ABCC1 or ABCG2. In mechanism-based studies, BMN-673 shows a competitive inhibition on the substrate drug efflux activity of ABCC1 or ABCG2. To further investigate the mechanism of BMN-673 resistance in ovarian cancer, the BMN-673-resistant subline A2780/T4 was constructed from human ovarian cancer cell line A2780 by drug selection with gradually increasing concentration. The upregulated ABCC1 and ABCG2 protein expression were observed on the plasma membrane of A2780/T4 cells, resulting in enhanced resistance to other ABCC1 or ABCG2 substrate drugs. Furthermore, the knockout of either ABCC1 or ABCG2 gene can increase sensitivity to BMN-673 in the A2780/T4 subline. Consistently, observations from in vivo experiments showed that the same drug-resistant characteristics could be retained in the tumor xenograft mice models. Taken together, BMN-673 is an MDR-susceptible agent due to its interactions with ABCC1 or ABCG2, and overexpression of ABCC1 or ABCG2 transporter may attenuate its therapeutic effect in cancer cells.

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