# Co-targeting BET Bromodomain Proteins and MNK Kinases in Pancreatic Cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $465,989

## Abstract

A growing body of research has now demonstrated that inhibitors targeting bromodomain and extra-terminal
domain (BET) proteins, which mediate mRNA transcription, have anti-tumor effects against pancreatic ductal
adenocarcinoma (PDAC). BET inhibitors can also normalize the PDAC stroma by suppressing the activation of
cancer-associated fibroblasts (CAFs). However, BET inhibitors induce Rac1-mediated activation of MNK
kinases, which mediate mRNA translation. Importantly, targeting MNK kinases and the MNK effector hnRNPA1
enhances the efficacy of BET inhibitors. Significantly, MNK inhibitors induce CD8+ T cell infiltration, but their
effector function is suppressed by the tumor-associated macrophages (TAMs). Notably, BET inhibitors can
decrease the infiltration of TAMs. The objective in this application is to elucidate the mechanisms by which the
combination of BET and MNK inhibitors demonstrates anti-tumor responses against PDAC. The central
hypothesis is that the combination effectively targets the cancer cells, modulates the tumor immune
microenvironment, and normalizes the pancreatic stroma to suppress PDAC growth. Three specific aims are
proposed: 1) Define and target negative feedback loops to enhance the anti-tumor effects of BET inhibitors in
vivo; 2) Evaluate the effects of the combination of BET and MNK inhibitors on CD8+ T cell infiltration and
activation; 3) Determine the effects of the combination of BET and MNK inhibitors on the pancreatic stroma.
Under the first aim, the mechanisms by which MNK effectors hnRNPA1 and CYFIP1, which can function
downstream of Rac1, limit the efficacy of BET inhibitors will be evaluated. Further, the efficacy of co-treatment
with BET and MNK inhibitors will be evaluated in organoid and transgenic mouse models of PDAC. For the
second aim, the effects of the combination therapy on CD8+ T cell infiltration and activation and macrophage
abundance and polarization will be evaluated. In addition, the contribution of MNK kinases and the MNK effectors
hnRNPA1 and CYFIP1 in macrophages to limiting the efficacy of BET inhibitors will be evaluated. In the third
aim, the effects of the combination therapy on the stromal reaction will be characterized in the transgenic mouse
model. The contribution of MNK kinases, CYFIP1, and hnRNPA1 in pancreatic CAFs to limiting the efficacy of
BET inhibitors will also be evaluated. In addition, the relationship between BET and MNK kinase activity, MNK
effectors, and stromal reaction will be evaluated in human PDAC tumor specimens. There are several innovative
elements in this proposal, including the novel therapeutic approach to enhance anti-tumor responses in PDAC
patients; novel concepts on how the combination therapy of BET and MNK inhibitors modulates the tumor
immune microenvironment and the stromal reaction for synergistic anti-tumor responses; and the unique
combination of complex models of PDAC, including in vivo orthotopic, organoid, and transgenic mouse models.
This propos...

## Key facts

- **NIH application ID:** 10795641
- **Project number:** 5R01CA265997-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Hidayatullah G. Munshi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,989
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795641

## Citation

> US National Institutes of Health, RePORTER application 10795641, Co-targeting BET Bromodomain Proteins and MNK Kinases in Pancreatic Cancer (5R01CA265997-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795641. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*