title: AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma.
abstract: OBJECTIVE
  Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard-of-care treatments for patients with HNSCC include surgery, radiation, and chemotherapy. In addition, the anti-EGFR monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult malignancy to treat. Thus, identification of new molecular targets is critical.
  
  
  METHODS
  In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient-derived xenografts (PDX), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small-molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard-of-care treatment regimens used in HNSCC.
  
  
  RESULTS
  AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases, and shorter relapse-free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. In addition, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation-resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance.
  
  
  CONCLUSIONS
  This study provides evidence for the role of AXL in HNSCC pathogenesis and supports further preclinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Toni M
authors.initials: TM
authors.lastname: Brand
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Mari
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Stein
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Kelsey L
authors.initials: KL
authors.lastname: Corrigan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Braverman
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: John P
authors.initials: JP
authors.lastname: Coan
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Pearson
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Harsh
authors.initials: H
authors.lastname: Bahrar
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Department of Medical Physics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Tyler L
authors.initials: TL
authors.lastname: Fowler
authors.affiliation: Department of Medical Physics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Bednarz
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Saha
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin.
authors.forename: David
authors.initials: D
authors.lastname: Yang
authors.affiliation: Departments of Medicine and Pathology, University of Southern California, Los Angeles, California.
authors.forename: Parkash S
authors.initials: PS
authors.lastname: Gill
authors.affiliation: Department of Pathology, University of Chicago Medical Center, Chicago, Illinois.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lingen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Saloura
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Villaflor
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Kimple
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. dlwheeler@wisc.edu.
authors.forename: Deric L
authors.initials: DL
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D014230:Triazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D001567:Benzocycloheptenes; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014230:Triazoles; C548378:bemcentinib; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase