title: AXL mediates resistance to cetuximab therapy.
abstract: The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (Ctx(R) cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in Ctx(R) cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in Ctx(R) cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers. Cancer Res; 74(18); 5152-64. ©2014 AACR.
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: Neha
authors.initials: N
authors.lastname: Luthar
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Toulany
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 Medicine, Division of Hematology/Oncology, 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; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D000068818:Cetuximab; D000094963:Axl Receptor Tyrosine Kinase