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BET Proteins as Attractive Targets for Cancer Therapeutics

Department of Rheumatology, Medical University of Lodz, 90-050 Lodz, Poland
Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
Author to whom correspondence should be addressed.
Academic Editor: Agnieszka Zdzislawa Robaszkiewicz
Int. J. Mol. Sci. 2021, 22(20), 11102;
Received: 2 September 2021 / Revised: 4 October 2021 / Accepted: 8 October 2021 / Published: 14 October 2021
(This article belongs to the Special Issue Transcription in Cancer Initiation and Progression)
Transcriptional dysregulation is a hallmark of cancer and can be an essential driver of cancer initiation and progression. Loss of transcriptional control can cause cancer cells to become dependent on certain regulators of gene expression. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate the expression of multiple genes involved in carcinogenesis. BET inhibitors (BETis) disrupt BET protein binding to acetylated lysine residues of chromatin and suppress the transcription of various genes, including oncogenic transcription factors. Phase I and II clinical trials demonstrated BETis’ potential as anticancer drugs against solid tumours and haematological malignancies; however, their clinical success was limited as monotherapies. Emerging treatment-associated toxicities, drug resistance and a lack of predictive biomarkers limited BETis’ clinical progress. The preclinical evaluation demonstrated that BETis synergised with different classes of compounds, including DNA repair inhibitors, thus supporting further clinical development of BETis. The combination of BET and PARP inhibitors triggered synthetic lethality in cells with proficient homologous recombination. Mechanistic studies revealed that BETis targeted multiple essential homologous recombination pathway proteins, including RAD51, BRCA1 and CtIP. The exact mechanism of BETis’ anticancer action remains poorly understood; nevertheless, these agents provide a novel approach to epigenome and transcriptome anticancer therapy. View Full-Text
Keywords: BET; BETi; cancer; DNA repair; homologous recombination; transcription BET; BETi; cancer; DNA repair; homologous recombination; transcription
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MDPI and ACS Style

Sarnik, J.; Popławski, T.; Tokarz, P. BET Proteins as Attractive Targets for Cancer Therapeutics. Int. J. Mol. Sci. 2021, 22, 11102.

AMA Style

Sarnik J, Popławski T, Tokarz P. BET Proteins as Attractive Targets for Cancer Therapeutics. International Journal of Molecular Sciences. 2021; 22(20):11102.

Chicago/Turabian Style

Sarnik, Joanna, Tomasz Popławski, and Paulina Tokarz. 2021. "BET Proteins as Attractive Targets for Cancer Therapeutics" International Journal of Molecular Sciences 22, no. 20: 11102.

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