BET Inhibitors Form a Growing Area of Epigenetic Cancer Research

William Pass, DVM
Published: Thursday, Jun 14, 2018
Bromodomains, a group of structurally similar proteins, serve as epigenetic “readers”— they recognize and bind acetylated lysine residues. The human body’s 40-plus bromodomains play a wide range of roles, including signal transduction in inflammatory pathways and transcription mediation.1

In 1992, researchers discovered the bromodomain and extraterminal domain (BET) family, responsible for controlling expression of key immune signals and oncogenic pathways.2,3 This family of proteins, with each member characterized by 2 bromodomains, includes bromodomain-containing protein 2 (BRD2), BRD3, BRD4, and bromodomain testis-associated protein.2

BET proteins were quickly recognized as possible therapeutic targets in cancer, but at the time, epigenetic therapy was viewed with skepticism. Could widespread regulators of transcription be blocked without also inflicting collateral damage on normal gene function? This question would be answered, years later, with the arrival of BET inhibitors, a type of small-molecule inhibitor.

In 2010, the BET inhibitor JQ1 showed activity in nuclear protein in testis midline carcinoma (NMC), a rare and highly aggressive cancer involving BRD4 or BRD3 activity.4 Instead of widespread downregulation with severe toxicity, the activity of JQ1 was contextual and specific to a small number of genes, suggesting that BET inhibitors could be a viable reality. Since then, the landscape has become increasingly active.

Current Landscape

At present, at least 10 BET inhibitors are under investigation, with over a dozen active clinical trials.5 Early research suggested that BET inhibitors would have the most impact on hematologic malignancies, but clinical trials show that restricted doses may be necessary for safety, particularly due to thrombocytopenia. This has triggered development of a second generation of BET inhibitors, which are more selective for particular bromodomains. These agents appear to be better tolerated but may be more specific to certain cancer types.6

Although solid tumors may not respond as markedly as hematologic malignancies, research suggests that BET inhibitors could work well in combination with existing therapies to overcome resistance mechanisms.7 Combination studies are under way for breast cancer, prostate cancer, melanoma, renal cell carcinoma, lung cancer, and more.8-10

Rapid progress in the development of BET inhibitors has created a surge of enthusiasm, but Guillaume Andrieu, PhD, and colleagues at the Cancer Research Center at Boston University School of Medicine in Massachusetts, have urged caution. In a 2016 journal article, they described the rapid transition into clinical trials as “reckless and likely to lead to adverse events [AEs].”2

The authors explained that a lack of basic science could prove risky, particularly because BET proteins have many roles beyond cancer, including repression of latent viruses such as HIV, insulin production, and T-cell differentiation. Each BET protein controls unique transcriptional pathways, sometimes with opposing effects from another BET protein. Early BET inhibitors block activity of all BET proteins (pan-BET inhibitors) with low selectivity, possibly increasing the likelihood of AEs.

“Providing selective compounds of individual BET proteins is a crucial challenge to understand...their biological roles,” Andrieu and colleagues added. Such compounds could “unravel the molecular mechanisms of their signaling.” Fortunately, upcoming research is focused on developing such highly selective agents, so these ambitions may soon be realized.7

Figure. Impact of BET Inhibitors on Cancer Pathways

Figure. Impact of BET Inhibitors on Cancer Pathways
Ac indicates acetylation; BET, bromodomain and extra-terminal; BD, bromodomain; BRD, bromodomain-containing proteins; CTM, C-terminal motif; ET, extraterminal; NPS, N-terminal cluster of phosphorylation sites; P, phosphorylation.
The BET family members are “readers” of acetylated lysines that activate the transcription of aberrant genes, leading to carcinogenic processes affecting the cell cycle, proliferation, stemness properties, metastatic spreading, and angiogenesis. Inhibition of BET activity is believed to disrupt these processes.
Ocaña A, Nieto-Jiménez C, Pandiella A. Oncotarget. 2017;8(41):71285-71291. doi: 10.18632/oncotarget.19744.


Mechanisms of Action

BET inhibitors competitively bind bromodomains on a BET protein, thereby blocking localization to chromatin, which in turn suppresses recruitment of transcriptional proteins and resultant neoplastic processes.7 These processes include angiogenesis, cell cycle control, cancer stem cells, proliferation, metabolism, and metastasis11,12 (Figure12). Studies have shown that BET inhibitors alter numerous pathways and expression of hundreds of genes, including MYC, E2F, FOSL1, WNT5A, JAG1, NOTCH1, AURKB, and cyclin D family genes. Emerging key areas of interest in BET inhibitor research include aspects of MYC downregulation and angiogenic control.

MYC-Dependent Pathways

BET inhibitors gained early recognition by downregulating MYC, a known oncogenic driver in most human cancers.13 MYC amplification promotes cell survival and division through induction of multiple pathways. Hematologic malignancies, in particular, are characterized by pathologic activation of c-Myc, an oncoprotein. Outside of transgenic models, c-Myc inhibition was unknown prior to the introduction of JQ1.

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