title: Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone.
abstract: Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Medical Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.|Present address: Laboratory of Cancer Biology and Genetics, CCR, NCI, Bethesda, MD, USA.
authors.forename: M Christine
authors.initials: MC
authors.lastname: Hollander
authors.affiliation: Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA.
authors.forename: Jeeva P
authors.initials: JP
authors.lastname: Munasinghe
authors.affiliation: Division of Veterinary Resources, NIH, Bethesda, MD, USA.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Brinster
authors.affiliation: Medical Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: Mercado-Matos
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Regales
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.affiliation: Surgical Neurology Branch, NINDS, NIH, Bethesda, MD, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
authors.forename: Marlan R
authors.initials: MR
authors.lastname: Hansen
authors.affiliation: Division of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gurgel
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001522:Behavior, Animal; D015195:Drug Design; D004428:Ear Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004432:Ear, Middle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009043:Motor Activity; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012888:Skull Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013701:Temporal Bone / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D000970:Antineoplastic Agents; D037721:Pulmonary Surfactant-Associated Protein C; C489679:SFTPC protein, human; D014598:Uteroglobin; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: EGFR; EGFR-targeted therapy; ear tumorigenesis; mouse model of adenomatous ear tumor