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)中发生突变。突变的克拉斯 癌蛋白被锁定在一种结构性活跃的GTP结合状态，该状态激活多个效应信号 导致PDAC启动、维护和进展的级联。直接瞄准KRAS的战略有 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 是目前最有希望进入临床的方向。特别是，相当大的努力 目前，人们的兴趣集中在Raf-MEK-ERK丝裂原活化蛋白激酶(MAPK)的抑制剂上。 卡斯卡德。然而，RAF和MEK抑制剂在RAS突变的癌症中表现出有限的活性，主要是由于 导致ERK重新激活的逃逸机制迅速出现。这些发现促使 ERK抑制剂的研究进展。其中，BVD-523，一种靶向ERK1和ERK2的小分子 亚纳摩尔范围，是进入肿瘤学临床试验的领先化合物。PDX是临床上最相关的 用于测试BVD-523的有效性和识别潜在内在(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旨在测试BVD-523的疗效 广泛的资料库105，临床注释的PDAC患者来源的异种移植物(PDX)。在我们的提案中，我们 计划开发有效的基于ERK抑制剂的疗法，并通过利用 我们广泛的PDX系列产品，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的蛋白质组学和功能鉴定 胰腺癌，2)克服肿瘤固有ERK抑制耐药性的试验组合方法 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群体的预测性生物标志物 这项研究。

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.