2. Academic Validation
  3. TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters

TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters

  • J Biol Chem. 2021 Oct;297(4):101162. doi: 10.1016/j.jbc.2021.101162.
Bryan M Webb 1,  Benjamin L Bryson 2,  Eduardo Williams-Medina 3,  Jessica R Bobbitt 4,  Darcie D Seachrist 2,  Lindsey J Anstine 1,  Ruth A Keri 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland Ohio, USA; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
  • 2 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
  • 3 Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland Ohio, USA.
  • 4 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland Ohio, USA.
  • 5 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland Ohio, USA; Department of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland Ohio, USA. Electronic address: kerir@ccf.org.
PMID: 34481843 DOI: 10.1016/j.jbc.2021.101162
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.

Keywords

ABCG2; CDK7; SY-1365; TGF-β; THZ1; TNBC; activin; cyclin-dependent kinase 7; multidrug transporters; triple-negative breast cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128587
    99.27%, CDK7抑制剂
    CDK
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