Targeting Epigenomic Regulators at the Replication Fork in PDAC

胰腺癌(PDAC)仍然是一个治疗挑战，使新的靶点得以确定 以及开发这种疾病的新治疗策略是至关重要的。我们的长期合作 目标是推进基于上下文的、基于机制的范例，以改进表观基因组学的使用 癌症中的抑制剂。表观基因组机制，以及它们的抑制剂，通常只在 它们在基因表达或间期的作用背景，即使它们在不同的 细胞周期的各个阶段。例如，在DNA复制过程中，不仅整个基因组 复制，但伴随的染色质结构也是复制的。因此，从概念上讲，DNA 复制是挑战基因组和表观基因组完整性的脆弱时刻，这依赖于 严重依赖于S阶段DNA复制检查点的正常运作和DNA损伤 应对(解甲返乡)是这一进程的关键组成部分。在肿瘤形成的早期，增殖率较高 由激活的癌基因驱动，如KRAS，触发复制应激(RS)，如果不能耐受，就会导致 细胞衰老或死亡。因此，RS耐受性对肿瘤的进展至关重要，但潜在的 机制仍然知之甚少。在这里，我们将检验表观基因组学的中心假设 调节子G9a通过与S期相互作用的机制促进PDAc对RS的耐受性 DRC-DDR途径，代表治疗学的可操作脆弱性。完成这些研究后， 通过以下方式显著推进了该领域：1.揭示了G9a在耐受 癌基因诱导的RS，肿瘤发生中的一个关键的未被研究的事件，2.提供了对 G9a在DDR信令中的作用如何保护复制分叉的完整性以提供额外的靶向 针对先天DDR缺陷患者子集的策略，以及3.利用 癌基因驱动的RS过程中的表观遗传调控因子作为与RS协同的机制机会 增强药物，如DDR抑制剂。总之，我们寻求扩大我们对新机制的研究 这代表了以前无法识别的癌细胞的可操作脆弱性。我们乐观地认为， 这项研究的结果将影响未来可能共享相似疗法的临床测试的计划 提供急需的、新颖的治疗PDAC的机制。

Pancreatic adenocarcinoma (PDAC) remains a therapeutic challenge, making the identification of new targets and development of novel treatment strategies for this disease of paramount importance. Our LONG-TERM GOAL is to advance context-dependent, mechanism-based paradigms for the improved use of epigenomic inhibitors in cancer. Epigenomic machinery, and hence their inhibitors, are typically only considered within the context of their actions in gene expression, or interphase, even though they are operational during different stages of the cell cycle. During the process of DNA replication, for instance, not only is the entire genome replicated, but the accompanying chromatin structure is duplicated as well. Thus, conceptually, DNA replication represents a vulnerable moment for challenging genomic and epigenomic integrity, which relies heavily on the proper functioning of the S-phase DNA replication checkpoint (DRC) and DNA damage response (DDR) as critical components of this process. Early in tumorigenesis, higher proliferation rates driven by activated oncogenes, such as KRAS, trigger replication stress (RS), which if not tolerated causes cell senescence or death. RS tolerance, consequently, becomes vital to tumor progression, yet the underlying mechanisms remain poorly understood. Here, we will test the CENTRAL HYPOTHESIS that the epigenomic regulator G9a promotes RS tolerance in PDAC via a mechanism which involves interactions with S-phase DRC-DDR pathways, representing actionable vulnerabilities for therapeutics. Completion of these studies will significantly advance the field by: 1. revealing mechanisms by which G9a functions in the tolerance to oncogene-induced RS, a key understudied event in tumorigenesis, 2. providing novel mechanistic insight into how G9a-mediated function in DDR signaling protects replication fork integrity to offer additional targeting strategies for the subset of patients with inherent DDR deficiencies, and 3. leveraging the function of epigenetic regulators during oncogene-driven RS as a mechanistic opportunity to synergize with RS- enhancing drugs, such as DDR-inhibitors. In summary, we seek to extend our studies on new mechanisms that represent previously unrecognized actionable vulnerabilities for cancer cells. We are optimistic that the outcome of this research will impact planning for future clinical testing of therapies that may share similar mechanisms to offer much-needed, novel treatments for PDAC.