Harnessing TNFa Signaling To Improve Therapeutic Response In Pancreatic Cancer

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PROJECT SUMMARY Effective treatment is an unmet and urgent need for patients with pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by mutations of the KRAS gene, which occurs in >95% of cases. However, targeting KRAS and its downstream signaling pathways, particularly the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway has been clinically unsuccessful due to rapid emergence of escape mechanism including autophagy. In this study, we made novel observation that MAPK inhibition (MAPKi) results in rapid and dramatic secretion of tumor necrosis factor alpha (TNF), which we found mediates both cell survival and death. Selective targeting of the pro-survival MAPKAPK2 (MK2) downstream f TNF signaling augments MAPKi-induced autophagy and cell death. To rigorously study these aspects, we have developed a 3-dimensional co-culture system to show that the anti-tumor effect of combined ERK and MK2 inhibitors is powerful enough to overcome the protection provided by adjacent cancer-associated fibroblasts (CAFs) and kill PDAC cells. We made observations that targeting MK2 induces favorable immunological changes that could potentiate checkpoint immunotherapy. The overarching goal of our proposal is to perform deeper and more comprehensive mechanistic studies to support development of novel therapeutic combinations that can be delivered to PDAC patients as clinical trials. To achieve this goal, we propose the following three Aims: 1. Aim 1: We will study the role of MK2 in autophagy in PDAC and CAFs using a new 3D spheroid culture system. We will determine the mechanism by which MAPKi-induces autophagy. Furthermore, we will identify new interacting partners of MK2 through a novel proteomic approach. 2. Aim 2: We will develop new genetic mouse models with conditional MK2-deletion to systematically dissect the role of MK2 in different cell types in PDAC progression and shaping the tumor microenvironment. 3. Aim 3: We will assess the combination of MK2 plus MAPKi and chemotherapy using a repertoire of thirty patient-derived xenograft models. We will perform additional studies using state-of-the art techniques and mouse models to develop novel immunotherapy regimens that will be rigorously tested.