LC-MS/MS analyses of human PDAC cell lines after treatment with a new SUMO inhibitor

Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with overall five-year survival of 8%. 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 tumor biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. To find MYC-associated dependencies we analyzed human PDAC expression datasets. We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway mark a PDAC subtype with worse prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to a novel SUMO inhibitor with a potential for further clinical development.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）总体五年生存率仅为8%，预后极差。传统联合化疗是胰腺导管腺癌治疗领域的重要进展，但该疾病存在多种亚型，其中诸多亚型对这类疗法展现出广泛的耐药性。基因组MYC扩增是一类独特的胰腺导管腺癌亚型，具有侵袭性极强的肿瘤生物学特性。现已明确，MYC的过度激活会催生可被治疗策略靶向利用的致癌依赖特性。为探寻与MYC相关的致癌依赖特性，本研究分析了人类胰腺导管腺癌的基因表达数据集。研究发现，在胰腺导管腺癌中，MYC与SUMO化修饰系统存在密切关联。SUMO通路的相关组分可作为一类预后更差的胰腺导管腺癌亚型的分子标志物；本研究同时提供证据表明，MYC的过度激活与对新型SUMO抑制剂的敏感性升高显著相关，这类抑制剂具备进一步临床开发的潜力。