期刊
SEMINARS IN CANCER BIOLOGY
卷 83, 期 -, 页码 487-502出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.semcancer.2020.12.022
关键词
Drug resistance; Epigenetic reprogramming; Cancer; DNA methylation; Histone modifications; 3D chromatin organization; Epigenome
类别
资金
- National Institutes of Health [R01GM112003, R21GM126532, R01CA232017, R01HL134780, R01HL145719, R21GM138824]
- John S. Dunn Foundation Collaborative Research Award
- Welch Foundation [BE-1913-20190330]
- American Cancer Society [RSG-16-215-01-TBE, RSG-18-043-01-LIB]
Drug resistance is a major obstacle in cancer treatment, and both genetic and epigenetic factors play a role in this process. Epigenetic reprogramming can lead to transcriptional plasticity in tumor cells, driving their transformation towards a persistent state. Targeting epigenetic reprogramming is a new strategy to prevent drug resistance, and combining epigenetic drugs with existing anticancer regimens can overcome resistance.
Drug resistance, either intrinsic or acquired, represents a major hurdle to achieving optimal therapeutic outcomes during cancer treatment. In addition to acquisition of resistance-conferring genetic mutations, accumulating evidence suggests an intimate involvement of the epigenetic machinery in this process as well. Recent studies have revealed that epigenetic reprogramming, such as altered expression or relocation of DNA/histone modulators accompanied with chromatin structure remodeling, can lead to transcriptional plasticity in tumor cells, thereby driving their transformation towards a persistent state. These persisters represent a pool of slow-growing cells that can either re-expand when treatment is discontinued or acquire permanent resistance. Targeting epigenetic reprogramming or plasticity represents a new strategy to prevent the emergence of drug-refractory populations and to enable more consistent clinical responses. With the growing numbers of drugs or drug candidates developed to target epigenetic regulators, more and more epigenetic therapies are under preclinical evaluation, early clinical trials or approved by FDA as single agent or in combination with existing antitumor drugs. In this review, we highlight latest discoveries in the mechanistic understanding of epigenetically-induced drug resistance. In parallel, we discuss the potential of combining epigenetic drugs with existing anticancer regimens as a promising strategy for overcoming cancer drug resistance.
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