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Collateral Sensitivity Associated with Multidrug-Resistance Protein 5 in Triple-Negative Breast Cancer

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Thesis(10.56 MB)

Date

2022

Authors

Supervisor

Li, Yan
Liu, Dong-Xu

Item type

Thesis

Degree name

Doctor of Philosophy

Journal Title

Journal ISSN

Volume Title

Publisher

Auckland University of Technology

Abstract

The multidrug resistance (MDR)-induced chemo- and targeted-therapeutic failure remains a pivotal obstacle to effective treatment against triple-negative breast cancer (TNBC). Our recent publications reviewed that the clinical trials that target ATP-Binding Cassette (ABC) transporters to reverse drug resistance have been disappointing despite the positive in vitro evidence. However, ABC transporters-associated collateral sensitivity (CS) is poorly understood and contributes to a promising novel therapeutic strategy to overcome MDR in breast cancer. In this study, we investigated olaparib accumulation and sensitivity in ABCC5-overexpressing HEK293 (HEK-MRP5) and ABCC5 gene knockout (KO) TNBC cell models. The potential upstream regulators of ABCC5 were also studied in the respective gene KO cell model. Overexpression of ABCC5 in HEK-MRP5 and TNBC cells (endogenously in MDA-MB-231 and BT549 cells) was associated with increased olaparib sensitivity. This vulnerability was not reversed by a model ABCC5 inhibitor benzbromarone. The low ABCC5 expression level in isogenic parental HEK293 and KO TNBC cells was associated with an olaparib-resistant phenotype. Molecular docking studies suggested non-covalent olaparib-ABCC5 interactions with high binding affinity. In conclusion, olaparib exerted selective CS on ABCC5-expressing BRAC1 wildtype TNBC cell lines (MDA-MB-231 and BT549) and these results may broaden the clinical indications of olaparib and/or lead to the novel combination therapies to resensitise tumour MDR in patients with TNBC.

Description

Keywords

CRISPR-Cas9, Triple-negative breast cancer, TNBC, olaparib, doxorubicin, collateral sensitivity, ABCC5, MRP5, multidrug-resistance protein 5

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DOI

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Permanent link

https://hdl.handle.net/10292/15055

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Doctoral Theses