MEK AND PI3K INHIBITION IN THE REGULATION OF PANCREATIC CANCER METABOLISM

绝大多数胰腺导管腺癌(PDAC)涉及KRAS(KRAS*)的激活突变，与其他KRAS*癌症一样，PDAC对临床上使用的现有治疗方法反应甚微。虽然目前还没有令人满意的KRAS*特异性药物，但MEK和PI3K(Meki和PI3Ki)途径的抑制剂正在进入临床试验，这是KRAS*介导的细胞体外转化所必需的。指导该项目的中心假设是，PDAC以冗余的方式利用PI3K和MEK途径来驱动肿瘤生长，并且这些途径的关键作用涉及调节肿瘤代谢。该提案的总体目标是确定Meki/PI3Ki对PDAC细胞信号、代谢和治疗反应的影响。这些努力将与研究MEK/PI3K信号的代谢生物标记物和确定治疗耐药机制相结合，这在未来的治疗试验中将是至关重要的。其目的是：1.确定MEK/PI3K抑制对PDAC的影响。基因工程小鼠模型以及具有基因组特征的器官型人类PDAC培养将被用于比较在人类PDAC中发现的肿瘤抑制基因突变的不同组合的背景下，由遗传或药物Meki/PI3Ki引起的细胞反应和信号通路改变。2.确定MEK/PISK抑制对PDAC代谢的影响。谷氨酰胺和葡萄糖是肿瘤细胞用于能量生成和合成代谢过程的主要营养物质。这些营养素对体内PDAC代谢的贡献以及Meki/PI3Ki对其利用的影响将通过一系列放射性同位素标记、分子成像和LC-MS方法来确定。这些研究将深入了解PDAC代谢的调节，并为这些途径的活性定义生物标志物。3.确定PDAC对Meki/PI3Ki的耐药机制。初步研究表明，小鼠PDAC模型最终将对Meki/PI3Ki产生获得性耐药。获得性耐药的机制将通过一系列的磷酸蛋白质组学和遗传分析来探索。此外，作为增加BI的一种手段

The vast majority of pancreatic ductal adenocarcinomas (PDAC) involve activating mutations in KRAS (KRAS*) and as with other KRAS* cancers, PDAC show minimal response to existing therapies used in the clinic. While no satisfactory KRAS*-speclfic drugs are currently available, inhibitors of MEK and PI3K (MEKi and PI3Ki)¿pathways necessary for KRAS*-mediated cellular transformation in vitro, are now being introduced into clinical trials. The central hypothesis guiding this project is that PDAC utilize the PI3K and MEK pathways In a redundant way to drive tumor growth and that a critical role for these pathways Involves the regulation of tumor metabolism. The overall goals of this proposal are to determine the impact of MEKi/PI3Ki on PDAC cell signaling, metabolism, and therapeutic response. These efforts will be coupled with an investigation of metabolic biomarkers for MEK/PI3K signaling and identification of mechanisms of therapeutic resistance which would be critical in future therapeutic trials. The Aims are: 1. Determine the impact of MEK/PI3K inhibition in PDAC. Genetically engineered mouse models as well as genomically characterized organotypic human PDAC cultures will be used to compare the cellular responses and signaling pathway alterations provoked by genetic or pharmacologic MEKi/PI3Ki against the backdrop of different combinations of tumor suppressor mutations found in human PDAC. 2. Determine the impact of MEK/PISK inhibition on PDAC metabolism. Glutamine and glucose are the main nutrients used by tumor cells for energy generation and for anabolic processes. The contribution of these nutrients to PDAC metabolism in vivo and the impact of MEKi/PI3Ki on their utilization will be determined using a series of radioisotope labeling, molecular imaging, and LC-MS approaches. These studies will give insight Into the regulation of PDAC metabolism and define biomarkers for the activity of these pathways. 3. Determine the mechanisms of resistance to MEKi/PI3Ki in PDAC. Preliminary studies indicate that mouse PDAC models will eventually develop acquired resistance to MEKi/PI3Ki. The mechanisms of acquired resistance will be explored by a series of phosphoproteomics and genetic analyses. In addition, as a means to increase the bi