# Role of FAT1 somatic mutations in aggressiveness of head and neck cancer

> **NIH NIH R03** · EMORY UNIVERSITY · 2022 · $169,248

## Abstract

PROJECT SUMMARY
This proposed R03 application responds to NIDCR PAR-20-046 announcement entitled “NIDCR Small Research
Grants for Analyses of Existing Genomics Data”. The project aims to identify significantly altered protein and
gene mutation, expression, signaling pathways, and immune regulatory networks mediated by or associated with
FAT1 mutations, which contribute to aggressiveness of head and neck squamous cell carcinoma (HNSCC). We
will use existing genomic and proteomic data from The Cancer Genome Atlas (TCGA), NCI’s Clinical Proteomic
Tumor Analysis Consortium (CPTAC), and other published databases to perform bioinformatics and biostatistics
analyses. The major functional impacts of identified molecules will be confirmed by appropriate biological assays,
ranked as potential biomarker candidates which will be validated using datasets with patient clinical outcome.
Recently, TCGA study reported a FAT1 mutation rate of 23% in HNSCC, which was higher in human papilloma
virus (HPV)-negative cancer. Wild-type FAT1 exhibits a tumor suppressor activity, and the majority of mutated
FAT1 genes are inactivated by missense or truncation, leading to altered or terminated gene products. However,
the role of FAT1 mutants in HNSCC oncogenesis and progression remain poorly understood. We and others
observed that FAT1 mutations were potentially correlated with response to a combination therapy with cetuximab
and CDX-3379 (a HER3 blocking antibody) in a phase I HNSCC clinical trial. Although both EGFR targeted
therapy and immune checkpoint inhibitors (ICIs) have improved HNSCC patients’ outcome, most patients either
do not benefit or have disease progression on these therapies. We hypothesize that FAT1 mutations may
modulate key molecules involved in growth, metastasis, angiogenesis, and immunomodulation, which
contribute to resistance to targeted therapies and ICIs and affect the prognosis of HNSCC. To support
this hypothesis, we have used TCGA genomics and proteomics databases and identified associations between
FAT1 mutations and altered protein expressions, with potential implications in modulation of cellular sensitivity
to EGFR targeted therapy and ICIs, cancer metastasis/angiogenesis, and immune regulatory proteins in the
HNSCC micro-environment. In this project, we propose two aims to test this hypothesis with a focus on FAT1
truncated/deletion mutants. Aim 1: To understand genomic, proteomic, and mechanistic functions of FAT1
mutations and their associated signaling pathways that regulate responses to targeted therapies and ICIs and
enhance metastasis/recurrence potential; Aim 2: To discover FAT1 mutation-associated biomarkers that are
correlated with sensitivity to targeted therapies of EGFR/HER3, VEGFR2, and ICIs and affect the prognosis of
HNSCC patients. At the conclusion of this project, we expect to provide strong evidence to support the role of
FAT1 mutations and associated pathways in promoting HNSCC progression. These data will be used fo...

## Key facts

- **NIH application ID:** 10510325
- **Project number:** 1R03DE032084-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Zhengjia Chen
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $169,248
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10510325

## Citation

> US National Institutes of Health, RePORTER application 10510325, Role of FAT1 somatic mutations in aggressiveness of head and neck cancer (1R03DE032084-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10510325. Licensed CC0.

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