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Updated: Jun 7, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
A BPTF Inhibitor That Interferes with the Multidrug Resistance Pump to Sensitize Murine Triple-Negative Breast Cancer
Melanie M Sinanian1, Afshan Rahman1, Ahmed M Elshazly1,2
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract:
Triple-negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger-containing transcription factor), was capable of sensitizing preclinical models of TNBC to chemotherapy in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with the inhibition of the P-glycoprotein (P-gp) efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump in a manner consistent with the inhibition of the pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in TNBC, that has not yet been successfully addressed by clinical efforts.
Insights
A novel compound, AU1, sensitizes triple-negative breast cancer (TNBC) to chemotherapy by inhibiting the P-glycoprotein (P-gp) efflux pump. This discovery offers a new strategy against multidrug resistance in TNBC.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents a poor prognosis due to aggressive behavior, metastasis, and resistance to chemotherapy.
- Autophagy promotion by the BPTF inhibitor AU1 was previously shown to sensitize TNBC models to chemotherapy.
Purpose of the Study:
- To identify additional mechanisms by which AU1 sensitizes triple-negative breast cancer to chemotherapy.
- To investigate the role of P-glycoprotein (P-gp) efflux pump inhibition by AU1.
Main Methods:
- In silico molecular docking studies were performed to assess AU1 binding to the P-gp efflux pump.
- Preclinical models of TNBC were utilized to evaluate the effects of AU1 on chemotherapy sensitization.
Main Results:
- AU1 was found to inhibit the P-glycoprotein (P-gp) efflux pump, contributing to chemotherapy sensitization in TNBC.
- Molecular docking indicated that AU1 binds to active sites of the P-gp pump, consistent with functional inhibition.
- This identifies a novel chemical structure targeting multidrug efflux in TNBC.
Conclusions:
- AU1 exhibits a dual mechanism of action in sensitizing TNBC to chemotherapy, involving autophagy promotion and P-gp efflux pump inhibition.
- Targeting P-gp efflux represents a promising, yet underexplored, strategy for overcoming drug resistance in triple-negative breast cancer.
- AU1 provides a novel chemical scaffold for developing new therapies against multidrug-resistant TNBC.
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