Research Project 2: Development of Synergetic EKR Combinations in PDAC

KRAS癌基因在约95%的胰腺导管腺癌（PDAC）中突变。突变的Kras 癌蛋白被锁定在一个组成型活性，GTP结合状态，激活多种效应信号 级联导致PDAC启动、维持和进展。直接针对KRAS的策略 在过去的三十年里没有成功，所以抑制KRas效应信号通路似乎 是目前临床上最有前途的方向。特别是， 并且现在的兴趣集中在Raf-MEK-ERK丝裂原活化蛋白激酶（MAPK）的抑制剂上 级联。然而，Raf和MEK抑制剂在RAS突变型癌症中显示出有限的活性，这主要是由于 ERK再激活的逃逸机制的迅速出现。这些发现促使 ERK抑制剂的开发。其中，BVD-523是一种靶向ERK 1和ERK 2的小分子， 是进入肿瘤临床试验的领先化合物。PDX是最具临床意义的 用于检测BVD-523疗效和鉴别潜在内在（即细胞自主）和 外源性（即肿瘤微环境）耐药机制，可用于开发更多 有效的组合疗法我们的研究项目2旨在使用我们的 105个临床注释的PDAC患者来源的异种移植物（PDX）的广泛储存库。在我们的建议中，我们 计划开发有效的基于ERK通路的疗法，结合预测性生物标志物， 我们广泛的PDX库，可以迅速进入临床试验。为了实现这一目标， 我们提出了以下三个目标：1）进行PDX的蛋白质基因组学和功能表征， 胰腺癌，2）测试克服肿瘤内在ERK抑制抗性的组合方法 机制，以及3）开发克服肿瘤外源性ERK的治疗组合方法 抑制抗性机制我们的目标是确定可以快速推进到 胰腺癌的临床试验和可用于丰富患者人群的预测性生物标志物， 书房

The KRAS oncogene is mutated in ~95% of pancreatic ductal adenocarcinomas (PDAC). Mutated Kras oncoproteins are locked in a constitutively active, GTP-bound state that activates multiple effector signaling cascades leading to PDAC initiation, maintenance, and progression. Strategies of directly targeting KRas have not been successful over the last three decades, so inhibition of KRas effector signaling pathways appears to be the most promising direction at the moment for advancement to the clinic. In particular, considerable efforts and interests are now focused on inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. However, Raf and MEK inhibitors have shown limited activity in RAS-mutant cancers, largely owing to the rapid emergence of the escape mechanism of ERK reactivation. These findings have prompted the development of ERK inhibitors. Among them, BVD-523, a small molecule that targets ERK1 and ERK2 in the sub-nanomolar range, is the leading compound entering oncology clinical trials. PDXs are the most clinicallyrelevant model for testing the efficacy of BVD-523 and identifying potential intrinsic (i.e cell-autonomous) and extrinsic (i.e tumor microenvironmental) resistance mechanisms that can be exploited for development of more potent combinatorial regimens. Our Research Project 2 aims at testing the efficacy of BVD-523 using our extensive repository of 105, clinically-annotated PDAC patient-derived xenografts (PDX). In our proposal, we plan to develop effective ERK inhibitor-based therapies in conjunction with predictive biomarkers by leveraging our extensive repertoire of PDXs, which can be rapidly advanced into clinical trials. To achieve this objective, we propose the following three aims: 1) undertake proteogenomic and functional characterization of PDXs of pancreatic cancer, 2) test combination approaches that overcome tumor-intrinsic ERK inhibition resistance mechanisms, and 3) develop therapeutic combination approaches that overcome tumor-extrinsic ERK inhibition resistance mechanisms. Our goal is to identify combinations that can be quickly advanced into clinical trials in pancreatic cancer and predictive biomarkers that can be used to enrich patients population for the study.