Epigenetic Therapeutics and Their Impact in Immunotherapy of Lung Cancer

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. Novel therapeutic developments are critically necessary to improve outcomes for this disease. Aberrant epigenetic change plays an important role in lung cancer development and progression. Therefore, drugs targeting the epigenome are being investigated in the treatment of lung cancer. Monotherapy of epigenetic therapeutics such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have so far not shown any apparent benefit while one of the clinical trials with the combinations of DNMTi and HDACi showed a small positive signal for treating lung cancer. Combinations of DNMTi and HDACi with chemotherapies have some efficacy but are often limited by increased toxicities. Preclinical data and clinical trial results suggest that combining epigenetic therapeutics with targeted therapies might potentially improve outcomes in lung cancer patients. Furthermore, several clinical studies suggest that the HDACi vorinostat could be used as a radiosensitizer in lung cancer patients receiving radiation therapy. Immune checkpoint blockade therapies are revolutionizing lung cancer management. However, only a minority of lung cancer patients experience long-lasting benefits from immunotherapy. The role of epigenetic reprogramming in boosting the effects of immunotherapy is an area of active investigation. Preclinical studies and early clinical trial results support this approach which may improve lung cancer treatment, with potentially prolonged survival and tolerable toxicity. In this review, we discuss the current status of epigenetic therapeutics and their combination with other antineoplastic therapies, including novel immunotherapies, in lung cancer management.