1. TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters
- Author
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Darcie D. Seachrist, Jessica R. Bobbitt, Bryan M. Webb, Lindsey J. Anstine, Eduardo Williams-Medina, Ruth A. Keri, and Benjamin L. Bryson
- Subjects
TGF-β ,multidrug transporters ,ABCG2 ,CDK7 ,EMT, epithelial to mesenchymal transition ,Triple Negative Breast Neoplasms ,Biochemistry ,TNBC, triple-negative breast cancer ,Downregulation and upregulation ,Cyclin-dependent kinase ,Transforming Growth Factor beta ,GSEA, Gene Set Enrichment Analysis ,Cell Line, Tumor ,TGF-β, transforming growth factor beta ,Gene silencing ,SY-1365 ,ATP Binding Cassette Transporter, Subfamily G, Member 2 ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,CDK, cyclin-dependent kinase ,Inhibin-beta Subunits ,cyclin-dependent kinase 7 ,biology ,Kinase ,ABC, ATP-binding cassette ,CDK7i, inhibitor of CDK7 ,activin ,Cell Biology ,Activin receptor ,Transforming growth factor beta ,FST, follistatin ,THZ1 ,Cyclin-Dependent Kinases ,Neoplasm Proteins ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Drug Resistance, Neoplasm ,embryonic structures ,biology.protein ,Cancer research ,triple-negative breast cancer ,Female ,Signal transduction ,TNBC ,Cyclin-Dependent Kinase-Activating Kinase ,Follistatin ,Research Article ,Signal Transduction - Abstract
Cyclin-dependent kinase 7 (CDK7) is a master regulatory kinase that drives cell cycle progression and stimulates expression of oncogenes in a myriad of cancers. Inhibitors of CDK7 (CDK7i) are currently in clinical trials; however, as with many cancer therapies, patients will most likely experience recurrent disease due to acquired resistance. Identifying targets underlying CDK7i resistance will facilitate prospective development of new therapies that can circumvent such resistance. Here we utilized triple-negative breast cancer as a model to discern mechanisms of resistance as it has been previously shown to be highly responsive to CDK7 inhibitors. After generating cell lines with acquired resistance, high-throughput RNA sequencing revealed significant upregulation of genes associated with efflux pumps and transforming growth factor-beta (TGF-β) signaling pathways. Genetic silencing or pharmacological inhibition of ABCG2, an efflux pump associated with multidrug resistance, resensitized resistant cells to CDK7i, indicating a reliance on these transporters. Expression of activin A (INHBA), a member of the TGF-β family of ligands, was also induced, whereas its intrinsic inhibitor, follistatin (FST), was repressed. In resistant cells, increased phosphorylation of SMAD3, a downstream mediator, confirmed an increase in activin signaling, and phosphorylated SMAD3 directly bound the ABCG2 promoter regulatory region. Finally, pharmacological inhibition of TGF-β/activin receptors or genetic silencing of SMAD4, a transcriptional partner of SMAD3, reversed the upregulation of ABCG2 in resistant cells and phenocopied ABCG2 inhibition. This study reveals that inhibiting the TGF-β/Activin-ABCG2 pathway is a potential avenue for preventing or overcoming resistance to CDK7 inhibitors.
- Published
- 2021