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Targeting Epigenetic Regulators in Cancer to Overcome Resistance to Targeted Therapy

  • Mukesh VermaEmail author
  • Vineet KumarEmail author
Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 20)

Abstract

Resistance to cancer therapy is an ongoing challenge, and there is a need to seek out non-traditional approaches such as targeting epigenetic components for cancer therapy. Epigenomics provides essential tools not only for therapeutic intervention but also as predictors of drug response. Unlike alteration of genetic components, where the structure of a gene is changed, such as mutations, deletions, additions, and single nucleotide polymorphisms, epigenetics changes gene expression without altering the genetic sequence. Furthermore, several epigenetic changes are reversible, and as a result, drugs have been developed that can reverse the epigenetic changes associated with different cancers. These epigenetic drugs target DNA methyltransferases, histone deacetylases and proteins associated with post-transcriptionally modified histones. Epigenetic regulators represent potential therapeutic targets as they often have binding domains that lend themselves well to small molecule inhibition. Here, we discuss factors that contribute to the development of resistance to targeted therapy and how epigenetic regulators can be utilized to overcome this resistance. We provide examples of several cancer types for which conventional targeted therapy has limited effects, but improved treatment outcomes are observed following epigenetic reprogramming of gene expression patterns, including modification of histones and DNA. Results from clinical trials have indicated the efficacy of epigenetic drugs as cancer therapy, mainly when administered in combination with traditional anticancer drugs. These promising data suggest that epigenetic drugs have great potential in controlling and treating cancer.

Keywords

Biomarker Epigenetics Epidemiology Histones Methylation Treatment 

Abbreviations

AUC

Area under curve

CDKN1

Cyclin-dependent kinase inhibitor 1

CRC

Colorectal cancer

CRPC

Castration resistant prostate cancer

CSCs

Cancer stem cells

DNMTs

DNA methyltransferases

EMT

Epithelial-to-mesenchymal transition

EZH2

Enhancer of zeste homolog 2

HATs

Histone acetyltransferases

HCC

Hepatocellular carcinoma

HDAC

Histone deacetylase

HER2

Human epidermal growth factor receptor

HY-PDT

Hypericin-mediated photodynamic therapy

KMTs

Histone lysine methyltransferases

LINE

Long interspersed nuclear elements

miRs

Micro RNAs

NaPB

3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

NSCLC

Non-small cell lung cancer

oncomiR

Oncogenic miRNAs

ORR

Overall response rate

PSA

Prostate-specific antigen

RCC

Renal cell carcinoma

SAHA

Suberoylanilide hydroximic acid

SINE

Short interspersed nuclear elements

TET

Ten-eleven translocation protein family

TSA

Trichostatin A

VEGF

Vascular endothelial growth factor

VPA

Valproic acid

Notes

Financial Disclosure

There is no financial conflict.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Methods and Technologies Branch, Epidemiology and Genomics Research Program, Division of Cancer Control and Population SciencesNational Cancer Institute, National Institutes of HealthBethesdaUSA
  2. 2.Department of PhysiologyNational University of SingaporeSingaporeSingapore

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