# Harnessing TNFa Signaling To Improve Therapeutic Response In Pancreatic Cancer

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $572,447

## Abstract

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.

## Key facts

- **NIH application ID:** 10817236
- **Project number:** 5R01CA262414-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kian H Lim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $572,447
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817236

## Citation

> US National Institutes of Health, RePORTER application 10817236, Harnessing TNFa Signaling To Improve Therapeutic Response In Pancreatic Cancer (5R01CA262414-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10817236. Licensed CC0.

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