Objective Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. Design We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. Results We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. Conclusion SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

中文翻译：

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SUMO 通路抑制靶向侵袭性胰腺癌亚型

目的 胰腺导管腺癌 (PDAC) 的预后仍然不佳，总体 5 年生存率为 9%。传统的联合化疗是 PDAC 治疗的明显进步；然而，该疾病的亚型存在，它们对此类疗法表现出广泛的抵抗力。基因组 MYC 扩增代表具有侵袭性肿瘤生物学的 PDAC 的一个独特子集。很明显，MYC 的过度激活会产生可用于治疗的依赖性。该研究的目的是发现并针对与 MYC 相关的依赖关系。设计 我们分析了人类 PDAC 基因表达数据集。结果通过使用免疫组织化学分析大型 PDAC 队列中的小泛素样修饰符 (SUMO) 途径得到证实。使用 SUMO 抑制剂并使用 PDAC 的人和鼠二维、类器官和体内模型进行表征。结果 我们观察到 MYC 连接到 PDAC 中的 SUMOylation 机制。SUMO 通路的组成部分表征了预后不佳的 PDAC 亚型，我们提供证据表明 MYC 的过度激活与对药理 SUMO 抑制的敏感性增加有关。结论 应该针对侵袭性 PDAC 亚型进一步开发基于 SUMO 抑制剂的疗法。