Projects per year
Abstract
Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.
Original language | English |
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Pages (from-to) | 123-139.e7 |
Number of pages | 25 |
Journal | Molecular Cell |
Volume | 82 |
Issue number | 1 |
DOIs | |
Publication status | Published - 6 Jan 2022 |
Keywords
- BRD4
- cancer
- CDK8
- chromatin
- combination therapy
- enhancer
- Mediator complex
- precision medicine
- synthetic lethality
- transcription
Projects
- 2 Finished
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Therapeutic targeting of the colorectal epigenome
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/20
Project: Research
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Mediator kinase as a therapeutic target for Wnt/B-catenin dependent malignancies
Firestein, R., Williams, B., Mathivanan, S. & Cain, J.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/17 → 31/12/20
Project: Research