FADD Functions as an Oncogene in Chr11q13.3-Amplified Head and Neck Squamous Cell Carcinoma

Chromosomal 11q13.3 amplification is the most common gene copy-number variation event in head and neck squamous cell carcinoma (HNSCC) that corresponds with poor prognosis. Although cyclin D1, a G1/S phase cell-cycle regulatory protein at this locus, is considered as a key driver of malignant progression, further exploration is needed to develop more effective targets for cases with this amplification. Using CRISPR-based gene knockout screening of genes located in chr11q13.3, we found that loss of the gene encoding the Fas-associated death domain (FADD) protein, a well-recognized adapter to caspase-8 that induces cell apoptosis, significantly reduced cancer cell proliferation. FADD expression was elevated in chr11q13.3-amplified tumors and correlated with poor prognosis. RNA sequencing, mass spectrometry, and proteomics analyses revealed a direct relationship between FADD and the DNA helicase MCM5 in the S phase. FADD and cyclin D1 acted at different stages of the cell cycle to synergistically induce proliferation, and caspase-8 deficiency was required for the oncogenic activity of FADD. In a patient-derived xenograft model with chr11q13.3 amplification, combined administration of the DNA helicase complex inhibitor and CDK4/6 inhibitor effectively curtailed tumor growth. Overall, this study identified a nonclassic oncogenic role for FADD in mediating tumor progression in HNSCC and provided a feasible treatment option for patients with chr11q13.3 amplification. Significance: FADD promotes progression of tumors with chr11q13.3 amplification by binding to the DNA helicase complex, which can be targeted in combination with cyclin D1 as a viable therapeutic strategy for HNSCC patients.