Aberrant Epigenetic Regulation: A Central Contributor to Lung Carcinogenesis and a New Therapeutic Target

Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at “epigenetically targeted” doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in “priming” patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years. KEY POINTS Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Identification of epigenetic aberrations provides prognostic information in early-stage lung cancer. Treatment of patients with non-small cell lung cancer with maximally tolerated doses of either demethylating agents or histone deacetylase inhibitors has not been a successful therapeutic strategy. Combinatorial treatment with lower doses of a demethylating agent and a histone deacetylase inhibitor has shown early promise as a new therapy for patients with lung cancer, either alone or as a primer to subsequent anticancer therapy. Evaluation of key gene promoter demethylation in the peripheral blood after treatment with combination epigenetic therapy provides a potential predictive biomarker.