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CpG Island Methylation and Drug Resistance

  • Chapter
Cancer Drug Resistance

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Covalent epigenetic modifications such as DNA hypermethylation and histone posttranslational modifications are associated with transcriptional inactivation of many genes and are important during tumor development and progression. Genes involved in key DNA damage response pathways, such as cell cycle control, apoptosis signaling, and DNA repair, can frequently become methylated and epigenetically silenced in tumors. This may lead to differences in intrinsic sensitivity of tumors to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, chemotherapy itself can exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Since the DNA sequences of epigenetically inactivated genes are not mutated but rather subject to reversible modifications via DNA methyltransferases (DNMTs) or histone modification, it is possible to reverse silencing using small molecule inhibitors. Such compounds show antitumor activity and can increase the sensitivity of drug-resistant preclinical tumor models. Clinical trials of epigenetic therapies are now underway. Epigenetic profiling, using DNA methylation and histone analysis, will provide guidance on optimization of these therapies with conventional chemotherapy and will help identify patient populations who may particularly benefit from such approaches.

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  1. Cancer Research UK Beatson Laboratories, Glasgow University, Glasgow, Scotland

    Robert Brown PhD

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  1. Jens M. Teodoridis PhD
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  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

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Teodoridis, J.M., Brown, R. (2006). CpG Island Methylation and Drug Resistance. In: Teicher, B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-035-5_19

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  • DOI: https://doi.org/10.1007/978-1-59745-035-5_19

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