Key Points
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Mutations in epigenetic regulatory genes are common in human cancers and are increasingly being recognized as attractive therapeutic targets.
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Gain-of-function mutations and overexpression can be targeted by small molecule inhibitors. Inhibitors of EZH2, DOT1L, KDM1A, isocitrate dehydrogenase 1 (IDH1), IDH2 and bromodomain and extra-terminal (BET) family proteins have shown promise in clinical trials.
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Loss-of-function mutations can be targeted through synthetic lethality. To date, potential therapies have been identified for cancers that are deficient in the switch/sucrose non-fermentable (SWI/SNF) complex, trimethylation of histone H3 lysine 36 (H3K36me3), CREB-binding protein (CBP), S-methyl-5′-thioadenosine phosphorylase (MTAP) and KDM6A.
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Owing to their roles in immune modulation, epigenetic therapies can modulate the efficacy of immunotherapies.
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Epigenetic inhibitors can also be used to overcome drug resistance.
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Biological complexity, context dependency, inhibitor selectivity and biomarker selection should be considered during the development of new epigenetic therapies.
Abstract
In the past few years, it has become clear that mutations in epigenetic regulatory genes are common in human cancers. Therapeutic strategies are now being developed to target cancers with mutations in these genes using specific chemical inhibitors. In addition, a complementary approach based on the concept of synthetic lethality, which allows exploitation of loss-of-function mutations in cancers that are not targetable by conventional methods, has gained traction. Both of these approaches are now being tested in several clinical trials. In this Review, we present recent advances in epigenetic drug discovery and development, and suggest possible future avenues of investigation to drive progress in this area.
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Acknowledgements
We thank members of the Ashworth laboratory, J. Esensten and J. Gordan for their helpful comments on the manuscript. Work in the Ashworth laboratory is supported by the US National Cancer Institute, Breast Cancer Research Foundation, S.G. Komen for the Cure and the BRCA Foundation.
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Competing interests
S.X.P. declares no competing interests. A.A. has patents on the use of PARP inhibitors held jointly with AstraZeneca and has benefitted financially (and may do so in the future) through the ICR Rewards to Inventors Scheme. A.A. is also a co-founder of Tango Therapeutics.
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Glossary
- Hypomethylation
-
Decreased methylation on DNA or histones. DNA hypomethylation usually occurs at repeated sequences of the genome and can result in genome instability and transcriptional alteration.
- Hypermethylation
-
Increased methylation on DNA or histones. DNA hypermethylation at gene promoters can result in transcriptional silencing.
- Demethylases
-
Enzymes that remove methyl groups from nucleic acids, proteins and other molecules.
- Methyltransferases
-
Enzymes that add methyl groups to nucleic acids, proteins and other molecules. Both DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs) use S-adenosylmethionine (SAM) as the methyl donor, and many HMT inhibitors are SAM-competitive.
- Histone H3.3
-
A histone H3 variant that is deposited at actively transcribed regions of chromatin. It is encoded by one of the two genes, H3F3A or H3F3B.
- Immune checkpoint inhibitors
-
Inhibitors against immune checkpoint proteins that keep immune responses in check and prevent T cells from killing cancer cells. These inhibitors are used in cancer treatments. Examples of targets include programmed cell death protein 1 (PD1)–programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4)–B7-1 (also known as CTLA4–CD80) or CTLA4–B7-2 (also known as CTLA4–CD83).
- Mono-, di- or trimethylation
-
(Denoted by me, me2 and me3). They represent the number of methyl groups on the lysine and arginine residues. Lysine residue can be mono-, di- or trimethylated, whereas arginine can be mono- or dimethylated.
- Polycomb repressive complex 2
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(PRC2). A Polycomb complex responsible for the di- and trimethylation of histone H3 lysine 27 (H3K27). The PRC2 core complex consists of EZH2, EED, SUZ12, RBBP7 and RBBP4.
- Cancer testis antigens
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A large family (with approximately 140 members) of tumour-associated antigens, which are expressed in various cancer types but not in normal tissues (except in the testis and placenta). They are usually highly immunogenic and are good immunotherapeutic targets.
- Adoptive T cell therapy
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A personalized cancer therapy that involves tumour-specific T cell isolation, ex vivo expansion and infusion into the same patient. The infused T cells can be naturally occurring tumour-reactive lymphocytes that were isolated from tumour-infiltrating lymphocytes (TILs), genetically engineered T cells expressing antitumour T cell receptors (TCRs) or chimeric antigen receptors (CARs).
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Pfister, S., Ashworth, A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov 16, 241–263 (2017). https://doi.org/10.1038/nrd.2016.256
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DOI: https://doi.org/10.1038/nrd.2016.256
