Myeloid Cell Leukemia 1 Small Molecule Inhibitor S63845 Synergizes with Cisplatin in Triple-Negative Breast Cancer.
Alexus ActonWilliam J PlaczekPublished in: Cancers (2023)
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.
Keyphrases
- cell death
- cell cycle arrest
- poor prognosis
- bone marrow
- acute myeloid leukemia
- small molecule
- pi k akt
- dna damage response
- signaling pathway
- cell therapy
- healthcare
- dendritic cells
- binding protein
- locally advanced
- palliative care
- cancer therapy
- gene expression
- long non coding rna
- mesenchymal stem cells
- dna repair
- pain management
- cell proliferation
- protein protein
- immune response
- radiation therapy
- drug delivery
- chronic pain
- health insurance
- heat stress