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

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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 for the development of a major grant application, such as an NIH R01, to elucidate the functional mechanisms of this prevalent mutation and develop new diagnosis or treatment strategies for HNSCC patients.