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Myeloid Cell Leukemia 1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Triple-Negative Breast Cancer
Alexus Acton1, William J Placzek1
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive cancer that lacks specific molecular targets that are often used for therapy. The refractory rate of TNBC to broad-spectrum chemotherapy remains high; however, the combination of newly developed treatments with the current standard of care has delivered promising anti-tumor effects. One mechanism employed by TNBC to avoid cell death is the increased expression of the anti-apoptotic protein, myeloid cell leukemia 1 (MCL1). Multiple studies have demonstrated that increased MCL1 expression enables resistance to platinum-based chemotherapy. In addition to suppressing apoptosis, we recently demonstrated that MCL1 also binds and negatively regulates the transcriptional activity of TP73. TP73 upregulation is a critical driver of cisplatin-induced DNA damage response, and ultimately, cell death. We therefore sought to determine if the coadministration of an MCL1-targeted inhibitor with cisplatin could produce a synergistic response in TNBC. This study demonstrates that the MCL1 inhibitor, S63845, combined with cisplatin synergizes by inducing apoptosis while also decreasing proliferation in a subset of TNBC cell lines. The use of combined MCL1 inhibitors with cisplatin in TNBC effectively initiates TAp73 anti-tumor effects on cell cycle arrest and apoptosis. This observation provides a molecular profile that can be exploited to identify sensitive TNBCs.
Insights
Triple-negative breast cancer (TNBC) is aggressive and hard to treat. Targeting myeloid cell leukemia 1 (MCL1) with S63845 and cisplatin synergizes to induce apoptosis and reduce proliferation in TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and lack of targeted molecular therapies.
- Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic protein overexpressed in TNBC, contributing to chemoresistance, particularly to platinum-based agents.
- MCL1 also inhibits the transcriptional activity of TP73, a key mediator of cisplatin-induced DNA damage response and apoptosis.
Purpose of the Study:
- To investigate the synergistic anti-tumor effects of combining an MCL1 inhibitor with cisplatin in TNBC.
- To elucidate the molecular mechanisms underlying the potential synergy between MCL1 inhibition and cisplatin treatment in TNBC.
Main Methods:
- Utilized TNBC cell lines to assess the in vitro effects of the MCL1 inhibitor S63845 in combination with cisplatin.
- Evaluated apoptosis, proliferation, and cell cycle arrest as key endpoints.
- Analyzed the role of TAp73 in mediating the anti-tumor response.
Main Results:
- The combination of S63845 and cisplatin demonstrated synergistic effects in a subset of TNBC cell lines.
- Co-treatment induced significant apoptosis and reduced cell proliferation.
- The synergistic effect was associated with the activation of TAp73-mediated anti-tumor responses, including cell cycle arrest and apoptosis.
Conclusions:
- Combined inhibition of MCL1 and cisplatin treatment offers a promising synergistic strategy for TNBC.
- The observed synergy is mediated through the reactivation of TAp73-dependent anti-tumor pathways.
- This study provides a molecular basis for identifying TNBC patients who may benefit from this combination therapy.
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