Elucidating the role of SHOC2 to enhance MEK inhibitor sensitivity in pancreatic cancer

项目摘要/摘要： 胰腺导管腺癌(PDAC)是一种致命的疾病，由于缺乏早期发现和治疗 有效的治疗方法。因此，迫切需要开发新的治疗策略。PDAC有一口井- 明确的突变格局，KRAS突变在绝大多数 临床病例。因此，针对KRAS及其下游通路的有效靶向治疗 一直备受追捧。在这些靶点中，下游的MEK1/2抑制已被证明是一种 对抗胰腺癌的前景看好的策略。然而，固有的和获得性的抗病机制 MEK抑制剂(Meki)已有报道。 为了更好地增强对KRAS突变癌症的MEK抑制，我们进行了一系列无偏见的基因组- 规模耗竭筛选以确定增强KRAS突变癌细胞对Meki治疗的新靶点 (曲美替尼)。在这些目标中，我们通过以下方式将SHOC2确定为一致和有效的选择性依赖 这一基因缺失导致了MEK敏化。进一步的功能验证研究揭示了SHOC2 基因敲除(KO)与Meki联合治疗导致了异种移植小鼠肿瘤生长的消融。SHOC2是 一种支架蛋白，通过与RAS、RAS效应器(RAF1/PI3K)等结合来促进RAS信号转导 下游监管机构。 根据我们的发现，我们假设SHOC2是一个新的、有效的致敏KRAS突变体的靶点 胰腺癌细胞通过RAS信号转导下游机制来抑制MEK。为了测试这一点 为了更好地理解SHOC2在调节Meki敏感性中的功能作用，我们建议： (1)确定SHOC2在PDAC中KRAS信号下游效应分子中的功能作用；(2) 确定SHOC2蛋白相互作用和调节Meki敏感性的功能结构域；(3)评估 SHOC2耗竭在临床相关的PDAC模型中的治疗相关性。拟议的研究将 开辟加强MEK抑制剂治疗改善胰腺癌生存结局的新途径 病人。

Project Summary/Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease due to the lack of early detection and effective therapies. Therefore, there is an urgent need to develop novel treatment strategies. PDAC has a well- defined mutational landscape, with mutations in KRAS being the most frequently found in the vast majority of clinical cases. Accordingly, effective targeted therapies against KRAS and its downstream pathways have been highly sought after. Among these targets, downstream MEK1/2 inhibition has been shown to be a promising strategy against pancreatic cancer. However, intrinsic and acquired mechanisms of resistance to MEK inhibitors (MEKi) have been reported. To better enhance MEK inhibition in KRAS mutant cancers, we conducted a series of unbiased genome- scale depletion screens to identify novel targets that enhance KRAS mutant cancer cells to MEKi treatment (trametinib). Among these targets, we identified SHOC2 as a consistent and effective selective dependency by which genetic deletion led to MEK sensitization. Further functional validation studies revealed SHOC2 knockout (KO) in combination with MEKi treatment led to ablation of tumor growth in xenograft mice. SHOC2 is a scaffolding protein that facilitates RAS signaling by binding to RAS, RAS effectors (RAF1/PI3K) and other downstream regulators. Based on our findings, we hypothesize that SHOC2 is a novel, potent target to sensitize KRAS mutant pancreatic cancer cells to MEK inhibitors through mechanisms downstream of RAS signaling. To test this hypothesis and better understand the functional role of SHOC2 in mediating MEKi sensitivity, we propose to: (1) Determine the functional role of SHOC2 on the downstream effectors of KRAS signaling in PDAC; (2) Determine SHOC2 protein interactions and functional domains that regulate MEKi sensitivity; (3) Evaluate the therapeutic relevance of SHOC2 depletion in clinically relevant models of PDAC. The proposed studies will open new avenues for enhancing MEK inhibitor therapy to improve the survival outcome of pancreatic cancer patients.