(621) FBXW7-NOTCH Signaling Determines Differentiation and Immune-Evasive Programs in HPV-Negative Head and Neck Squamous Cell Carcinoma

Introduction: Head and neck squamous cell carcinoma (HNSCC) accounts for most head and neck cancers. Its molecular and anatomic heterogeneity play a role in the presentation and progression of patients with HNSCC. Dysfunction in the HNSCC cellular state is thought to play a major role in its progression with the NOTCH family (NOTCH1,2,3,4) of genes contributing to dedifferentiation. NOTCH1 mutations have been reported in approximately 10 percent of HNSCC patients. The NOTCH family is known to be regulated by FBXW7, a substrate-recognition component of the SCF-type E3 ubiquitin ligase complex, playing a role in the proteasomal degradation of numerous oncogenes. Understanding the mechanism by which the NOTCH-FBXW7 axis plays a role in tumor differentiation and immune evasion will help design targeted therapies in patients with differential NOTCH activity or mutation status.

Methods: The Cancer Genome Atlas (TCGA) data for HNSCC was extracted for mutations in NOTCH1, 2, 3, 4, and FBXW7. Non-synonymous tumor mutation burden (TMB), perineural invasion, angiolymphatic invasion, differentiation programs, and immune-evasive programs in HPV-negative HNSCC patients were analyzed. Quantitative PCR was performed in HNSCC cell lines to analyze the NOTCH1 target genes. HES1, HEY1, differentiation genes, and tumor immune genes were also investigated.

Results: NOTCH1 has been shown previously to cooperate with p63 and regulate differentiation program in keratinocytes and HNSCC. We observed a significant negative correlation (p < 0.01) between FBXW7 and differentiation marker genes (early and late differentiation markers, Keratin 1, 10, and LORICRIN). We also observed a negative correlation between FBXW7 and two interferon regulatory factor (IRF) genes. Suggesting its immune evasive mechanism in HNSCC.

Conclusions: The NOTCH1–FBXW7 axis is an important therapeutic vulnerability in a subset of HNSCC, with the potential to reactivate tumor immune and differentiation programs, thereby improving patient survival.