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

胰腺导管腺癌(PDAC)的5年生存率只有11%，是一种预后不佳的疾病。PDAC的发病率和死亡率正在上升，并描述了年轻患者发病率增加的趋势。适度有效的联合化疗是大多数PDAC患者的标准治疗方案。在大多数患者中，对这些治疗没有任何反应。因此，迫切需要新的治疗方法。PDAC中存在两种共识亚型。所谓的基底细胞样亚型与疾病的间充质亚型重叠，对目前的治疗方法高度耐药。在我们的前期工作中，我们在高通量药物筛选中观察到，人和小鼠的PDAC细胞，随着E(内皮)到M(间充质)-T(转换)程序的激活，对HDAC抑制剂Panobinostat更敏感。帕诺比坦是FDA批准的异羟肟酸PAN-HDAC抑制剂。通过将全基因组的表观遗传学数据与Panobinostat的敏感性联系起来，我们观察到Panobinostat与不同类别的内源性逆转录病毒(ERV)之间的相关性。我们推测，已经显示出一定程度的开放染色质和低DNA甲基化的ERV可能是Panobinostat的靶标。Panobinostat对间充质细胞ERV的强烈抑制导致双链RNA(DsRNA)的产生增加，通过模式识别受体(PRR)感知，干扰素反应，并增强细胞杀伤。因此，我们的目标是系统地分析ERV对HDAC抑制的反应，研究Panobinostat触发的基于dsRNA的细胞应答，并通过合理的组合促进ds-RNA-INF应答。因此，我们的研究将增加对ERV对治疗反应的贡献的认识，并将建立ERV作为精确表观遗传治疗的生物标志物。

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.