Epigenetics as a mechanism driving polygenic clinical drug resistance

Abstract

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such ‘one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance.

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

“…Our results indicate that several methylation changes are directly associated with chemosensitization induced by demethylating agents combined with HDAC inhibitors. Similar observations have been reported in other tumour types (Chang et al, 2010); however, our data also reveal that epigenetic alterations associated with sensitivity to cisplatin occur at a few selected genes rather than at large numbers of loci in this cell line model (Glasspool et al, 2006). The group of epigenetically inactivated genes was upregulated by DAC and also the combined DAC and Belinostat treatment, but remained unaffected by Belinostat alone, with the exception of GLUL.…”

Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin

“…4 -8). The absence of convincing evidence that genetic changes have a role in acquired clinical resistance following anticancer therapy undermines the genetic hypothesis (5). In contrast, conclusive data show that increased resistance of cancer cells to chemotherapeutic agents is associated with epigenetic alterations that include changes in DNA methylation and histone modifications (4,5,7).…”

Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo

“…One example of this is epigenetic inactivation of the CpG island at the DNA repair gene, MGMT and response of glioma to monofunctional alkylating agents such as temozolomide (Hegi et al, 2005). DNA methylation and epigenetic silencing of tumour cells can also be selected for during chemotherapy and may be an important driving force behind acquired drug resistance (Glasspool et al, 2006). The MLH1 protein, part of the human DNA mismatch repair system, has been shown to be important in determining sensitivity to a number of important chemotherapeutic agents including alkylating agents and cisplatin (Fink et al, 1998;Brown, 1999).…”