Achieving clinical success with BET inhibitors as anti-cancer agents

• 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
• DOI: 10.1038/s41416-021-01321-0

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.