化学诱导PDEdelta降解作为KRAS突变型胰腺癌的新型治疗手段

胰腺癌是一种致死率高的恶性肿瘤，5年生存率仅有8%。KRAS突变是胰腺癌典型的分子特征，但目前仅稀有的G12C突变的KRAS可以靶向。免疫调节类药物是典型的分子胶水类药物，利用Glutarimide环劫持CRL4(CRBN)E3连接酶促进白血病细胞生存依赖的转录因子的泛素化降解而起到治疗作用。我们将Glutarimide环连接在不同的结构上，合成了一个的化合物库，并通过非标记定量质谱和热位移质谱发现了化合物PB1能够诱导PDEdelta的泛素化降解。PDEdelta是KRAS膜定位和发挥原癌活性的必需蛋白。我们计划从以下三个方面进行研究：1）阐明PDEdelta是新的PB1介导的CRBN的直接底物；2）阐明PB1通过促进PDEdelta的泛素化降解而阻止KRAS的信号传导；3）筛选PB1的协同致死基因突变。化学诱导PDEdelta降解有望成为一种新型的KRAS突变型胰腺癌的治疗手段。

Pancreatic cancer is a leading cause of cancer death, with a merely 8% five-year patient survival. KRAS gene mutations represent a hallmark genetic feature of pancreatic cancer. However, mutant KRAS proteins except the minority KRAS(G12C) are currently undruggable. Imunomodulatory drugs are a molecular glue type of compounds that hijack the CRL4（CRBN）ubiquitin ligase with their glutarimide ring to degrade neosubstrates essential for leukemia cell growth. We have synthesized a chemical library with a fixed glutarimide conjugated to diverse scaffold structures, and identified a novel compound PB1 that induces PDEdelta for proteasomal degradation, using label-free quantitative mass spectrometry (MS) and CETSA (cellular thermal shift assay)-MS assays. PDEdelta is a chaperone protein essential for KRAS membrane localization and thereby its oncogenic activity. Here we propose to test three specific aims: 1) To demonstrate PDEdelta is a direct neosubstrate recruited by PB1 to CRL4(CRBN) for ubiquitination; 2) To demonstrate PB1-induced PDEdelta degradation blocks KRAS oncogenic signaling; 3) To screen for and explore synthetic lethal mutations in KRAS mutant pancreatic cancer cells in combination with PB1. Chemical-induced degradation of PDEdelta may become a novel therapy against KRAS mutant pancreatic cancer.