Cancer is not only driven by genetic abnormalities (Hanahan & Weinberg, 2011), but also by epigenetic changes, involving DNA methylation and histone modifications (Herman & Baylin, 2003; Jones & Baylin, 2002). Epigenetic changes may addict cancer cells to altered signaling, resulting in growth advantage and drug resistance.
Methylation of CpG islands in promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes (Razin & Kantor, 2005). Several analyses have found specific tumor suppressor genes to be regularly affected by promoter hypermethylation and silencing in lung cancer, including epigenetic inactivation of HIC1 (hypermethylated in cancer 1), resulting in deacetylation of p53 and defective apoptotic response to DNA damage (Chen et al, 2005). Several studies report promoter hypermethylation in several genes in human NSCLC, for example the putative metastasis suppressor gene death-associated protein (DAP) kinase (Esteller et al, 1999; Tang et al, 2000), the platinum-drug detoxification gene glutathione S-transferase P1 (GSTP1) (Esteller et al, 1999), or the DNA repair gene 6-methylguanine-DNA-methyl-transferase (MGMT) (Esteller et al, 1999). Hypermethylation of the DAP kinase promoter was associated with poor survival in patients with stage I NSCLC (Tang et al, 2000), as was hypermethylation of the adenomatous polyposis coli (APC) tumor suppressor gene promoter in 91 NSCLC patients (Brabender et al, 2001). Promoter hypermethylation was found in another study in tumor samples of 98 patients with NSCLC to be the predominant mechanism in the silencing of DNA-repair genes (Lee et al, 2007). Low mRNA and protein expression of BRCA1, BRCA2, and XRCC5 as a result of DNA methylation was associated with impaired clinical outcome. Treatment with 5-Aza-2’-deoxycytidine (5-AZA) resulted in demethylation and reexpression of the BRCA1 and BRCA2 genes and reduced proliferation.
Drugs that act on the chromatin structure such as DNA demethylating drugs and histone-deacetylase inhibitors (HDACi) have real potential as epigenetic modulators (Egger et al, 2004; Issa et al, 2005). Preclinical work showed that re-expression of specific DNA regions could be achieved by 5-aza-20-deoxycytidine (5-AZA), a DNA methyltransferase inhibitor, and/or by histone deacetylase inhibitors (HDACi) (Cameron et al, 1999). For example, concurrent 5-AZA and entinostat in pretreated patients with recurrent, metastatic NSCLC was well tolerated and resulted in objective responses and a favourable OS of 6.4 months (Juergens et al, 2011). Four out of 19 patients had major tumor shrinkage following subsequent anticancer therapy given immediately after epigenetic targeting (Juergens et al, 2011). In conclusion, there is good evidence for the importance of epigenetic silencing of specific genes for the induction and progression of lung cancer, and epigenetic therapy is of particular interest for resensitization of lung tumors to chemotherapy.
Cancer is not only driven by genetic abnormalities (Hanahan & Weinberg, 2011), but also by epigenetic changes, involving DNA methylation and histone modifications (Herman & Baylin, 2003; Jones & Baylin, 2002). Epigenetic changes may addict cancer cells to altered signaling, resulting in growth advantage and drug resistance.
Methylation of CpG islands in promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes (Razin & Kantor, 2005). Several analyses have found specific tumor suppressor genes to be regularly affected by promoter hypermethylation and silencing in lung cancer, including epigenetic inactivation of HIC1 (hypermethylated in cancer 1), resulting in deacetylation of p53 and defective apoptotic response to DNA damage (Chen et al, 2005). Several studies report promoter hypermethylation in several genes in human NSCLC, for example the putative metastasis suppressor gene death-associated protein (DAP) kinase (Esteller et al, 1999; Tang et al, 2000), the platinum-drug detoxification gene glutathione S-transferase P1 (GSTP1) (Esteller et al, 1999), or the DNA repair gene 6-methylguanine-DNA-methyl-transferase (MGMT) (Esteller et al, 1999). Hypermethylation of the DAP kinase promoter was associated with poor survival in patients with stage I NSCLC (Tang et al, 2000), as was hypermethylation of the adenomatous polyposis coli (APC) tumor suppressor gene promoter in 91 NSCLC patients (Brabender et al, 2001). Promoter hypermethylation was found in another study in tumor samples of 98 patients with NSCLC to be the predominant mechanism in the silencing of DNA-repair genes (Lee et al, 2007). Low mRNA and protein expression of BRCA1, BRCA2, and XRCC5 as a result of DNA methylation was associated with impaired clinical outcome. Treatment with 5-Aza-2’-deoxycytidine (5-AZA) resulted in demethylation and reexpression of the BRCA1 and BRCA2 genes and reduced proliferation.
Drugs that act on the chromatin structure such as DNA demethylating drugs and histone-deacetylase inhibitors (HDACi) have real potential as epigenetic modulators (Egger et al, 2004; Issa et al, 2005). Preclinical work showed that re-expression of specific DNA regions could be achieved by 5-aza-20-deoxycytidine (5-AZA), a DNA methyltransferase inhibitor, and/or by histone deacetylase inhibitors (HDACi) (Cameron et al, 1999). For example, concurrent 5-AZA and entinostat in pretreated patients with recurrent, metastatic NSCLC was well tolerated and resulted in objective responses and a favourable OS of 6.4 months (Juergens et al, 2011). Four out of 19 patients had major tumor shrinkage following subsequent anticancer therapy given immediately after epigenetic targeting (Juergens et al, 2011). In conclusion, there is good evidence for the importance of epigenetic silencing of specific genes for the induction and progression of lung cancer, and epigenetic therapy is of particular interest for resensitization of lung tumors to chemotherapy.
