# FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $348,301

## Abstract

Project summary/Abstract
The long-term goal of this project is to improve therapeutic options for patients with
cholangiocarcinoma by better understanding the pathways that drive disease and increase
resistance to therapy. Worldwide, liver cancer is now second only to lung cancer for cancer-
related deaths. Cholangiocarcinoma is a primary liver cancer with rising incidence and few
effective treatment options. The current project will investigate canonical and non-canonical
fibroblast growth factor receptor-4 (FGFR4) signaling in cholangiocarcinoma initiation and
progression. Preliminary data demonstrated that cholangiocarcinoma cells exhibited autocrine
FGFR4 signaling through expression and secretion of the ligand FGF19. Inhibition of this
pathway increased apoptosis and decreased cell growth with effects at the G1/S checkpoint,
S phase duration, and mitosis. FGFR4 is strongly expressed in tumor tissue compared to
normal bile ducts. FGFR inhibition markedly reduced tumor size in rats and knockdown of
FGFR4 prevented subcutaneous tumor formation. We have identified a novel proteolytic
cleavage product of the full-length receptor that is composed of the intracellular domain (R4-
ICD). R4-ICD contains the C-terminal tyrosine kinase domain, activated AKT, and prevented
apoptosis. The central hypothesis of this proposal is that signaling through FGFR4 and R4-ICD
drives cholangiocarcinoma initiation, progression, and chemoresistance. Experiments in aim 1
will determine how malignant features are promoted by R4-ICD and FGFR4. Aim 2 will identify
tumor-initiating mechanisms of FGFR4 and R4-ICD. The third aim will demonstrate the role
FGFR4 and R4-ICD in chemotherapy resistance. Successful completion of this project will
increase our understanding of how FGFR4 promotes cholangiocarcinoma progression and
resistance to therapy, define new biology of R4-ICD, and test treatment strategies that inhibit
FGFR4 processing or kinase activity.

## Key facts

- **NIH application ID:** 9841386
- **Project number:** 5R01CA222649-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Justin L. Mott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,301
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841386

## Citation

> US National Institutes of Health, RePORTER application 9841386, FGFR4 intracellular domain promotes tumor progression in cholangiocarcinoma (5R01CA222649-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9841386. Licensed CC0.

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