# Therapeutic targeting of FGF19-driven cancers with FGF21 variants

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $383,156

## Abstract

ABSTRACT
Liver cancer is the most rapidly increasing cancer in the United States. Hepatocellular carcinoma (HCC), the
most common type of primary liver cancer with limited treatment options, accounts for about 75% of all liver
cancer and 30,000 deaths per year. Despite recent FDA approval of several new drugs for the treatment of
advanced liver cancer, five-year survival rate for HCC patients still remains to be around 20 percent, highlighting
the need to develop better therapeutic options. Aberrant expression of Fibroblast Growth Factor 19 (FGF19) has
been recently identified as an oncogenic driver in a subset of HCC patients. FGF19 is an ileum-derived
enterokine that belongs to endocrine Fibroblast Growth Factor (FGF) family, which normally functions as an
endocrine hormone and signals though FGF receptor (FGFR) pathway in the presence of obligate receptor, β-
Klotho. Overexpression of FGF19 in liver, however, promotes uncontrolled proliferation through FGF19-FGFR4-
β-Klotho pathway in an autocrine-paracrine manner. Our previous studies revealed that β-Klotho recognizes
FGF19 in the same manner as it recognizes FGF21, another member of endocrine FGF family with no mitogenic
properties, and that the molecular interactions between β-Klotho and FGF21 or FGF19 occur at the identical
interface. Based on our mechanistic understanding of cellular signaling by FGF19 and FGF21, we hypothesize
that FGF21 variants with enhanced binding affinities to β-Klotho will be able to effectively compete with FGF19
and consequently inhibit aberrant FGF19 signaling in cancers. The aims of this proposal seek to address this
overall hypothesis by (1) performing in-depth analyses of FGF21 variants using biophysical, biochemical, and
structural studies, (2) testing their capacity to inhibit FGF19 signaling and block proliferation of FGF19-driven
cancers, and (3) examining the abilities of FGF21 variants to overcome/prevent the resistance to kinase inhibitors
currently in clinical trials. The outcome of our studies will provide deeper mechanistic and biological
understanding of FGF19 signaling in cancers and offer novel means to prevent and treat FGF19-driven cancers.

## Key facts

- **NIH application ID:** 10521444
- **Project number:** 1R01CA258867-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sangwon Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,156
- **Award type:** 1
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521444

## Citation

> US National Institutes of Health, RePORTER application 10521444, Therapeutic targeting of FGF19-driven cancers with FGF21 variants (1R01CA258867-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10521444. Licensed CC0.

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