Abstract
Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1’s role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer’s genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) arise mainly from mucosal surfaces of the oral cavity, oropharynx, pharynx, larynx, and sinonasal cavity
The repeat regions extending from EGF8 to EGF12 have been implicated in ligand binding based on experimental manipulation and X-ray crystallography [47], so mutations in these In T cell acute lymphoblastic leukemia (T-ALL) cases (Figure 3), we found many more missense/INDEL mutations in the hetero-dimerization domains (HDs) domain than expected by chance (n = 768 out of 843) (35), which was consistent with previous studies demonstrating that missense and in-frame mutations in this domain activate NOTCH1 signaling
A challenge to developing targeted therapy for HNSCC is the dominance of mutations in tumor suppressors including NOTCH1, which is mutated in about 17% of human papillomavirus (HPV)-negative HNSCC
Summary
Head and neck squamous cell carcinomas (HNSCCs) arise mainly from mucosal surfaces of the oral cavity, oropharynx, pharynx, larynx, and sinonasal cavity. NOTCH1 signaling is initiated in a juxtacrine fashion through binding to one of five canonical ligands (Jagged-1 (JAG1), JAG2, Delta-like ligand 1 (DLL1), DLL3, and DLL4) expressed on the surface of neighboring cells. These ligands interact with extracellular epidermal growth factor (EGF)-like repeat binding domains spanning extracellular NOTCH1, causing conformational changes that open up NOTCH1 to cleavage by a disintegrin and metalloproteinase (ADAM) and subsequently the γ-secretase complex [28,29,30]. DSL, Delta/Serrate/Lag-2; VWC, von Willebrand factor type C domain; PDZ, PSD-95/Dlg/ZO-1
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