Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor <i>BRAF</i> gene mutations but lack mutations in <i>KRAS, NRAS,</i> or <i>MEK1</i>
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- Kadoaki Ohashi
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
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- Lecia V. Sequist
- Massachusetts General Hospital Cancer Center, Boston, MA 02114;
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- Maria E. Arcila
- Department of Pathology,
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- Teresa Moran
- Catalan Institute of Oncology, Universitat Autonoma de Barcelona and Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Barcelona, Spain;
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- Juliann Chmielecki
- Weill Cornell Graduate School of Medical Sciences, New York, NY 10065;
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- Ya-Lun Lin
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
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- Yumei Pan
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
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- Lu Wang
- Department of Pathology,
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- Elisa de Stanchina
- Anti-Tumor Assessment Core Facility, and
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- Kazuhiko Shien
- Department of Thoracic Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan;
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- Keisuke Aoe
- Departments of iMedical Oncology and
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- Shinichi Toyooka
- Department of Thoracic Surgery, Okayama University Hospital, Okayama, Okayama 700-8558, Japan;
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- Katsuyuki Kiura
- Department of Hematology, Oncology, and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Okayama 700-8558, Japan;
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- Lynnette Fernandez-Cuesta
- Max Planck Institute for Neurological Research with Klaus Joachim Zülch Laboratories of the Max Planck Society and the Medical Faculty, Cologne 50931, Germany;
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- Panos Fidias
- Massachusetts General Hospital Cancer Center, Boston, MA 02114;
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- James Chih-Hsin Yang
- Graduate Institute of Oncology and
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- Vincent A. Miller
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
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- Gregory J. Riely
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
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- Mark G. Kris
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
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- Jeffrey A. Engelman
- Massachusetts General Hospital Cancer Center, Boston, MA 02114;
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- Cindy L. Vnencak-Jones
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232; and
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- Dora Dias-Santagata
- Pathology, Harvard Medical School, Boston, MA 02115;
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- Marc Ladanyi
- Department of Pathology,
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- William Pao
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232;
説明
<jats:p> Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic <jats:italic>EGFR</jats:italic> -mutant lung cancers. Here, we modeled disease progression using <jats:italic>EGFR</jats:italic> -mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary <jats:italic>NRAS</jats:italic> Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because <jats:italic>RAS</jats:italic> / <jats:italic>RAF</jats:italic> / <jats:italic>MEK</jats:italic> mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary <jats:italic>KRAS/NRAS/BRAF/MEK1</jats:italic> gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent <jats:italic>NRAS</jats:italic> , <jats:italic>KRAS,</jats:italic> or <jats:italic>MEK1</jats:italic> mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant <jats:italic>NRAS</jats:italic> or <jats:italic>BRAF</jats:italic> in drug-sensitive <jats:italic>EGFR</jats:italic> -mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 109 (31), E2127-, 2012-07-06
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1360002217132005504
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- ISSN
- 10916490
- 00278424
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- データソース種別
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- Crossref
- KAKEN