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MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Jeffrey A. Engelman,1,2,3Kreshnik Zejnullahu,4,5Tetsuya Mitsudomi,6Youngchul Song,2,3Courtney Hyland,7Joon Oh Park,4,5Neal Lindeman,7Christopher-Michael Gale,3Xiaojun Zhao,5James Christensen,8Takayuki Kosaka,6Alison J. Holmes,4,5Andrew M. Rogers,5Federico Cappuzzo,9Tony Mok,10Charles Lee,7Bruce E. Johnson,4,5Lewis C. Cantley,2,3Pasi A. Jänne4,5*
The epidermal growth factor receptor (EGFR) kinase inhibitorsgefitinib and erlotinib are effective treatments for lung cancerswith EGFR activating mutations, but these tumors invariablydevelop drug resistance. Here, we describe a gefitinib-sensitivelung cancer cell line that developed resistance to gefitinibas a result of focal amplification of the MET proto-oncogene.inhibition of MET signaling in these cells restored their sensitivityto gefitinib. MET amplification was detected in 4 of 18 (22%)lung cancer specimens that had developed resistance to gefitinibor erlotinib. We find that amplification of MET causes gefitinibresistance by driving ERBB3 (HER3)–dependent activationof PI3K, a pathway thought to be specific to EGFR/ERBB familyreceptors. Thus, we propose that MET amplification may promotedrug resistance in other ERBB-driven cancers as well.
1 Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. 2 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. 3 Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. 4 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. 6 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan. 7 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. 8 Pfizer Global Research and Development, Department of Research Pharmacology, La Jolla Laboratories, La Jolla, CA 92121, USA. 9 Istituto Clinico Humanitas, Department on Hematology-Oncology, Rozzano 20089, Italy. 10 Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
* To whom correspondence should be addressed. E-mail: pjanne{at}partners.org
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Y. Yang, M. Wislez, N. Fujimoto, L. Prudkin, J. G. Izzo, F. Uno, L. Ji, A. E. Hanna, R. R. Langley, D. Liu, et al. (2008)
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An In vivo Model of Met-Driven Lymphoma as a Tool to Explore the Therapeutic Potential of Met Inhibitors.
P. Accornero, G. Lattanzio, T. Mangano, R. Chiarle, R. Taulli, F. Bersani, P. E. Forni, S. Miretti, C. Scuoppo, W. Dastru, et al. (2008)
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EGFR Antagonists in Cancer Treatment.
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Differential Responses to Erlotinib in Epidermal Growth Factor Receptor (EGFR)-Mutated Lung Cancers With Acquired Resistance to Gefitinib Carrying the L747S or T790M Secondary Mutations.
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Met Receptor Contributes to Trastuzumab Resistance of Her2-Overexpressing Breast Cancer Cells.
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|Abstract »|Full Text »|PDF »
Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells.
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Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better.
Signal Strength Dictates Phosphoinositide 3-Kinase Contribution to Ras/Extracellular Signal-Regulated Kinase 1 and 2 Activation via Differential Gab1/Shp2 Recruitment: Consequences for Resistance to Epidermal Growth Factor Receptor Inhibition.
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Signaling networks assembled by oncogenic EGFR and c-Met.
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PNAS
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Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor.
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Collagen I Promotes Epithelial-to-Mesenchymal Transition in Lung Cancer Cells via Transforming Growth Factor Signaling.
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Emerging Therapies for Non-small Cell Lung Cancer.
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ASCO Educational Book
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MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.
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PNAS
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|Abstract »|Full Text »|PDF »
Proapoptotic BH3-Only BCL-2 Family Protein BIM Connects Death Signaling from Epidermal Growth Factor Receptor Inhibition to the Mitochondrion.
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