Methylation Biomarkers of Drug Resistance in Cancer
The association of the methylation status of DNA repair genes such as O(6)- Methylguanine-DNA Methyltransferase (MGMT) and MLH1 illustrate the two main mechanisms of response to DNA damaging agents. Loss of methylation of MGMT, and the subsequent increase in gene expression, leads to a reduction in response to alkylating agents as a result of enhanced repair of drug-induced DNA damage. Conversely, the increase in methylation of MLH1 and its resulting loss of expression has been consistently observed in drug-resistant tumor cells. MLH1 encodes a mismatch repair enzyme activated in response to DNA damage; activation of MLH1 also induces apoptosis of tumor cells, and thus loss of its expression leads to resistance to DNA-damaging agents. Other methylation-regulated genes that could serve as biomarkers in cancer therapy include drug transporters, genes involved in microtubule formation and stability, and genes related to hormonal therapy response. These methylation biomarkers have potential applications for disease prognosis, treatment response prediction, and the development of novel treatment strategies for cancer.
STAT3 and Resistance to Cisplatin
STAT3 (Signal transducer and activator of transcription 3) seems to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. STAT3 is central to determining the type of inflammation that can either promote or inhibit tumor development, direct inhibition of STAT3 may represent a promising therapeutic target to reprogram tumor-promoting inflammation into tumor-suppressing inflammation (Kato 2011). STAT3 is elevated in ~82% of head and neck cancers and has been associated with cisplatin resistance. STAT3 inhibitors such as FLLL32 (a compound based on curcumin) may be useful adjuvants to cisplatin to overcome drug resistance (Abuzeid et al. 2011).