Achieving clinical success with BET inhibitors as anti-cancer agents

The transcriptional upregulation of oncogenes is a driving force behind the progression of many tumours. However, until a decade ago, the concept of ‘switching off’ these oncogenic pathways represented a formidable challenge. Research has revealed that members of the bromo- and extra-terminal domain...

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Bibliographic Details
Published in:British journal of cancer Vol. 124; no. 9; pp. 1478 - 1490
Main Authors: Shorstova, Tatiana, Foulkes, William D., Witcher, Michael
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.04.2021
Nature Publishing Group
Subjects:
631/67/1059/602
692/53/2423
Antineoplastic Agents - therapeutic use
Antitumor agents
Biomarkers
Biomedical and Life Sciences
Biomedicine
Cancer Research
Chromatin
Drug Resistance
Epidemiology
Humans
Molecular Medicine
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Oncology
Prognosis
Proteins - antagonists & inhibitors
Review
Review Article
Transcription
Transcription Factors - antagonists & inhibitors
Tumors
ISSN:0007-0920, 1532-1827, 1532-1827
Online Access:Get full text
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Summary:The transcriptional upregulation of oncogenes is a driving force behind the progression of many tumours. However, until a decade ago, the concept of ‘switching off’ these oncogenic pathways represented a formidable challenge. Research has revealed that members of the bromo- and extra-terminal domain (BET) motif family are key activators of oncogenic networks in a spectrum of cancers; their function depends on their recruitment to chromatin through two bromodomains (BD1 and BD2). The advent of potent inhibitors of BET proteins (BETi), which target either one or both bromodomains, represents an important step towards the goal of suppressing oncogenic networks within tumours. Here, we discuss the biology of BET proteins, advances in BETi design and highlight potential biomarkers predicting their activity. We also outline the logic of incorporating BETi into combination therapies to enhance its efficacy. We suggest that understanding mechanisms of activity, defining predictive biomarkers and identifying potent synergies represents a roadmap for clinical success using BETi.
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-021-01321-0