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Clinical trials for BET inhibitors run ahead of the science
Guillaume Andrieu1, Anna C Belkina2, Gerald V Denis3
1Department of Medicine, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, United States.
Abstract:
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles.
Insights
BET inhibitors target cancer cells but lack selectivity, potentially causing adverse effects by impacting vital functions and reactivating latent viruses like HIV. Further research is needed for safer, targeted cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Clinical trials are investigating small molecule inhibitors of BET bromodomain proteins for cancer treatment.
- BRD4 inhibition is pursued for its anti-proliferative effects, particularly its cooperation with the MYC oncogene.
- Current BET inhibitors lack selectivity for BRD4 among BET proteins (BRD2, BRD3), which have overlapping and distinct functions.
Purpose of the Study:
- To highlight the lack of BET protein selectivity in current inhibitors.
- To emphasize the diverse biological functions of BET proteins beyond cancer proliferation.
- To caution against clinical trials without a deeper understanding of BET protein functions and potential adverse events.
Main Methods:
- Review of existing literature on BET inhibitors and their targets.
- Analysis of the functional roles of BET proteins (BRD2, BRD3, BRD4) in various biological pathways.
- Assessment of potential risks associated with non-selective BET inhibition, including viral reactivation.
Main Results:
- No available BET inhibitor is selective for BRD4 over BRD2 and BRD3.
- BET proteins regulate critical cellular processes including insulin production, immune responses, and viral latency.
- BET inhibitors have demonstrated potential to reactivate latent viruses such as HIV.
Conclusions:
- Proceeding with clinical trials for non-selective BET inhibitors without full mechanistic understanding is potentially reckless.
- A deeper understanding of BET protein functions is crucial for developing targeted cancer therapies.
- Further basic science research is needed to identify relevant cancer targets and predict side effect profiles for BET inhibitors.
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