title: Molecular pathways in head and neck cancer: EGFR, PI3K, and more.
abstract: The treatment of head and neck squamous cell carcinoma (HNSCC) is set to undergo rapid changes, as novel treatment targets informed by genomic profiling and novel molecularly targeted therapies continue to make strides. In this review we provide an overview of the latest developments regarding (1) EGFR targeting for HNSCC, (2) PI3K as a novel treatment target, and (3) newly described key genetic events in HNSCC such as NOTCH1 mutations and emerging candidate targets including ALK1 and hedgehog. The first molecular targeting strategy to demonstrate a survival advantage for patients with HNSCC has emerged in the context of EGFR biology. Cetuximab remains the only U.S. Food and Drug Administration (FDA)-approved targeted therapy available for HNSCC, but EGFR as a target has not been individualized in this disease. The PI3K-AKT pathway is downstream of EGFR and is emerging as potentially one of the most important pathways in HNSCC. PIK3CA is the most frequently mutated oncogene for HNSCC (approximately 20%) and may play a role for both HPV-negative and HPV-positive tumors. Multiple therapeutic strategies targeting PI3K are being explored, and multiple agents either alone or in combination are in development. NOTCH1 is a key tumor suppressor gene and its genetic alterations lead to abnormal pathway activation. ALK1 is a novel target involved in angiogenesis, and efficacy in patients with HNSCC was documented in an early inhibitor trial. The hedgehog pathway modulates EGFR dependence and epithelial to mesenchymal transition (EMT), a key invasion and drug-resistance mechanism in HNSCC.
authors.affiliation: From the Department of Medicine, Section of Medical Oncology, Attikon University Hospital, Athens, Greece; Department of Medicine, University of Chicago School of Medicine and Biological Sciences, Chicago, IL; Division of Medical Oncology, University of Colorado School of Medicine, Denver, CO.
authors.forename: Amanda
authors.initials: A
authors.lastname: Psyrri
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D000068818:Cetuximab / Q000627:therapeutic use; D058534:Class I Phosphatidylinositol 3-Kinases; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D030301:Activin Receptors, Type II; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D053823:Hedgehog Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1; C497761:NOTCH1 protein, human; C484760:PIK3CA protein, human; C425364:ACVRL1 protein, human