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Cell and Tumor Biology

Aberrant Epidermal Growth Factor Receptor Signaling and Enhanced Sensitivity to EGFR Inhibitors in Lung Cancer

Joseph Amann, Shailaja Kalyankrishna, Pierre P. Massion, Joyce E. Ohm, Luc Girard, Hisayuki Shigematsu, Michael Peyton, Denise Juroske, Yuhui Huang, J. Stuart Salmon, Young H. Kim, Jonathan R. Pollack, Kiyoshi Yanagisawa, Adi Gazdar, John D. Minna, Jonathan M. Kurie and David P. Carbone
Joseph Amann
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Shailaja Kalyankrishna
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Pierre P. Massion
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Joyce E. Ohm
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Luc Girard
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Hisayuki Shigematsu
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Michael Peyton
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Denise Juroske
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Yuhui Huang
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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J. Stuart Salmon
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Young H. Kim
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Jonathan R. Pollack
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Kiyoshi Yanagisawa
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Adi Gazdar
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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John D. Minna
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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Jonathan M. Kurie
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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David P. Carbone
1Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; 3Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas; 4Department of Pathology, Stanford University School of Medicine, Stanford, California; and 5Aichi Cancer Center, Nagoya, Japan
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DOI:  Published January 2005
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Abstract

Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non–small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC. Treatment with the specific EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib or the EGFR inhibitory antibody cetuximab induced apoptosis of HCC827, a NSCLC cell line with EGFR gene amplification and an exon 19 deletion. H1819, a NSCLC cell line that expresses high levels of EGFR, ErbB2, and ErbB3 but has wild-type EGFR, showed intermediate sensitivity to TKIs. In both cell lines, ligand-induced receptor tyrosine phosphorylation was delayed and prolonged and AKT was constitutively phosphorylated (but remained inhibitable by EGFR TKI). Thus, in addition to EGFR mutations, other factors in NSCLC cells, such as high expression of ErbB family members, may constitutively activate AKT and sensitize cells to EGFR inhibitors.

  • Lung cancer
  • Epidermal growth factor receptor
  • Received September 8, 2004.
  • Revision received October 5, 2004.
  • Accepted November 4, 2004.
  • ©2005 American Association for Cancer Research.
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Cancer Research: 65 (1)
January 2005
Volume 65, Issue 1
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Aberrant Epidermal Growth Factor Receptor Signaling and Enhanced Sensitivity to EGFR Inhibitors in Lung Cancer
Joseph Amann, Shailaja Kalyankrishna, Pierre P. Massion, Joyce E. Ohm, Luc Girard, Hisayuki Shigematsu, Michael Peyton, Denise Juroske, Yuhui Huang, J. Stuart Salmon, Young H. Kim, Jonathan R. Pollack, Kiyoshi Yanagisawa, Adi Gazdar, John D. Minna, Jonathan M. Kurie and David P. Carbone
Cancer Res January 1 2005 (65) (1) 226-235;

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Aberrant Epidermal Growth Factor Receptor Signaling and Enhanced Sensitivity to EGFR Inhibitors in Lung Cancer
Joseph Amann, Shailaja Kalyankrishna, Pierre P. Massion, Joyce E. Ohm, Luc Girard, Hisayuki Shigematsu, Michael Peyton, Denise Juroske, Yuhui Huang, J. Stuart Salmon, Young H. Kim, Jonathan R. Pollack, Kiyoshi Yanagisawa, Adi Gazdar, John D. Minna, Jonathan M. Kurie and David P. Carbone
Cancer Res January 1 2005 (65) (1) 226-235;
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