Epidermal growth factor receptor as a novel molecular target for aggressive papillary tumors in the middle ear and temporal bone
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Shigeru Kawabata1, M. Christine Hollander2,13, Jeeva P. Munasinghe3, Lauren R. Brinster4, José R. Mercado-Matos2, Jie Li5, Lucia Regales6, William Pao7, Pasi A. Jänne8, Kwok-Kin Wong8, John A. Butman9, Russell R. Lonser10, Marlan R. Hansen11, Richard K. Gurgel12, Alexander O. Vortmeyer5 and Phillip A. Dennis1
1 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2 Medical Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
3 Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD, USA
4 Division of Veterinary Resources, NIH, Bethesda, MD, USA
5 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
6 Memorial Sloan-Kettering Cancer Center, New York, USA
7 Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
9 Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA
10 Surgical Neurology Branch, NINDS, NIH, Bethesda, MD, USA
11 Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
12 Division of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, UT, USA
13 Present address: Laboratory of Cancer Biology and Genetics, CCR, NCI, Bethesda, MD, USA
Shigeru Kawabata, email:
Phillip A. Dennis, email:
Keywords: mouse model of adenomatous ear tumor, ear tumorigenesis, EGFR, EGFR-targeted therapy
Received: January 22, 2015 Accepted: February 13, 2015 Published: March 15, 2015
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.
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