Connecting HDAC inhibitor sensitivity of an aggressive PDAC subtype to endogenous retroviral elements

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With a 5-year survival rate of only 11%, Pancreatic Ductal Adenocarcinoma (PDAC) remains a disease with a dismal prognosis. Incidence and mortality rates of PDAC are rising and a trend for an increased incidence in younger patients is described. Modestly effective combination chemotherapies are standard-of-care for most patients with PDAC. No response to these therapies is observed in the majority of patients. Therefore, novel therapies are urgently needed. Two consensus subtypes exist in PDAC. The so-called basal-like subtype, which overlaps the mesenchymal subtype of the disease, is highly resistant to current therapies. In our preliminary work, we observed in a high-throughput drug screen, that human and murine PDAC cells, with activation of an E(pithelial)-to-M(mesenchymal)-T(Transition) program, were more sensitive to the HDAC inhibitor Panobinostat. Panobinostat is an FDA-approved hydroxamic acid pan-HDAC inhibitor. By connecting genome-wide epigenetic data to Panobinostat sensitivity, we observed a correlation between Panobinostat and distinct classes of endogenous retroviruses (ERVs). We hypothesize that ERVs, which already display somewhat open chromatin and low DNA methylation are likely targets of Panobinostat. Strong ERV de-repression by Panobinostat in mesenchymal cells results in enhanced production of double-stranded RNA (dsRNA), sensing by pattern recognition receptors (PRR), an interferon response, and augmented cell killing. Therefore, we aim to systematically analyze ERV regulation in response to HDAC inhibition, investigate the Panobinostat-triggered dsRNA-based cellular response, and boost the ds-RNA-INF response by rational combinations. Therefore, our study will increase knowledge of the contribution of ERV to the therapy response and will establish ERV as biomarkers for precise epigenetic therapies.