<i>MECP2-</i> Dependent Cancers Can Be Targeted by Epigenetic Drugs: A New Role for Epigenetic Cancer Therapy

The methyl CpG-binding protein 2 (MECP2) gene has copy-number gain in a number of human cancers and functions as an oncogene through an unusual epigenetic mechanism. We explored the possibility that MECP2 might be a therapeutic target and whether its epigenetic mode of action is amenable to specific therapy. Constitutively expressed or inducible lentiviral short hairpin RNA directed at MECP2 in human triple-negative breast cancer (TNBC) cell lines with high or low level of MECP2 protein were grown as xenografts to assess oncogene addiction. We next evaluated the effect of DNA methylation inhibitors or histone deacetylase inhibitors on monolayer or soft agar growth of isogenic human mammary epithelial cells with or without MECP2 overexpression and xenograft growth of MECP2-dependent or MECP2-independent human TNBC or lung cancer cell lines. We then investigated the mechanism of MECP2-induced activation of the MAPK pathway and assessed the effect of drug treatment. Human cancer cell lines with MECP2 overexpression show MECP2 dependence, and epigenetic drugs are effective in these models. Activated RAS and other activators of the MAPK pathway caused resistance to these therapies, giving insight into their novel mode of action and demonstrating specificity. The kinase PAK3 is important for MECP2-mediated induction of the MAPK pathway, is modulated by epigenetic drugs affecting MECP2 action as expected, and may itself be a therapeutic target for MECP2-driven cancers. These preclinical studies show that tumors overexpressing MECP2 might benefit from epigenetic therapy targeting MECP2 function and demonstrate a novel mechanism of action for these drugs.