An Integrated Genomic and Epigenomic Approach Predicts Therapeutic Response to Zebularine in Human Liver Cancer

Drug-induced transcription and epigenetic changes can predict whether liver cancer can be successfully treated with an epigenome-targeting drug. A Crystal Ball for Cancer Therapy If you ask most first-year medical students, they are not likely to list fortune-telling as a required skill for a successful clinician. Yet, predicting how different patients will respond to therapy could save time, money, and lives. Andersen et al. peer into their crystal ball and provide an approach for determining whether patients with liver cancer will respond to treatment or not. Liver cancer causes more than half a million deaths annually. Although early cases may respond to treatment, it is often diagnosed at later stages when symptoms become more severe. Only a subset of patients with advanced-stage liver cancer is eligible for the most successful current therapy, sorafenib, leaving a large number of patients with few options. Epigenetic changes, or changes in gene expression not due to differences in DNA sequence, contribute to the initiation and progression of liver cancer. These changes are reversible, and epigenetic modifier drugs such as zebularine can reactivate tumor suppressor genes and decrease tumor cell growth. Andersen et al. characterized the epigenetic changes induced by zebularine in liver cancer cell lines. They found a distinct signature that identified two groups of cells—those sensitive and those resistant to zebularine. In an animal xenograft model, zebularine treatment of liver tumors with the “sensitive” profile resulted in increased survival and decreased metastasis to the lungs. Moreover, the zebularine-sensitive signature predicted prognosis of patients with liver cancer with an accuracy ranging from 84 to 96%. Therefore, this study not only provides a proof of principle that epigenetic modification may be a viable therapy for liver cancer but also gives us a glimpse into the future, allowing clinicians to predict clinical outcome for liver cancer patients, as well as the success or failure of this emerging treatment regimen. Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome.