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Science 316 (5827): 1039-1043

Copyright © 2007 by the American Association for the Advancement of Science

MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling

Jeffrey A. Engelman,1,2,3 Kreshnik Zejnullahu,4,5 Tetsuya Mitsudomi,6 Youngchul Song,2,3 Courtney Hyland,7 Joon Oh Park,4,5 Neal Lindeman,7 Christopher-Michael Gale,3 Xiaojun Zhao,5 James Christensen,8 Takayuki Kosaka,6 Alison J. Holmes,4,5 Andrew M. Rogers,5 Federico Cappuzzo,9 Tony Mok,10 Charles Lee,7 Bruce E. Johnson,4,5 Lewis C. Cantley,2,3 Pasi A. Jänne4,5*

Abstract: The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug 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}

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Downregulation of HER3 by a Novel Antisense Oligonucleotide, EZN-3920, Improves the Antitumor Activity of EGFR and HER2 Tyrosine Kinase Inhibitors in Animal Models.
Y. Wu, Y. Zhang, M. Wang, Q. Li, Z. Qu, V. Shi, P. Kraft, S. Kim, Y. Gao, J. Pak, et al. (2013)
Mol. Cancer Ther. 12, 427-437
   Abstract »    Full Text »    PDF »
DNA-Mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): A Catalog of Clinically Relevant Cancer Mutations to Enable Genome-Directed Anticancer Therapy.
P. Yeh, H. Chen, J. Andrews, R. Naser, W. Pao, and L. Horn (2013)
Clin. Cancer Res. 19, 1894-1901
   Abstract »    Full Text »    PDF »
Hepatocyte Growth Factor Sensitizes Brain Tumors to c-MET Kinase Inhibition.
Y. Zhang, K. E. Farenholtz, Y. Yang, F. Guessous, C. G. diPierro, V. S. Calvert, J. Deng, D. Schiff, W. Xin, J. K. Lee, et al. (2013)
Clin. Cancer Res. 19, 1433-1444
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistant Disease.
K. Ohashi, Y. E. Maruvka, F. Michor, and W. Pao (2013)
J. Clin. Oncol. 31, 1070-1080
   Abstract »    Full Text »    PDF »
Role of Epidermal Growth Factor Receptor Inhibitors in Epidermal Growth Factor Receptor Wild-Type Non-Small-Cell Lung Cancer.
S. A. Laurie and G. D. Goss (2013)
J. Clin. Oncol. 31, 1061-1069
   Abstract »    Full Text »    PDF »
MET As a Possible Target for Non-Small-Cell Lung Cancer.
A. A. Sadiq and R. Salgia (2013)
J. Clin. Oncol. 31, 1089-1096
   Abstract »    Full Text »    PDF »
ALK in Lung Cancer: Past, Present, and Future.
A. T. Shaw and J. A. Engelman (2013)
J. Clin. Oncol. 31, 1105-1111
   Abstract »    Full Text »    PDF »
Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancers.
H. A. Yu and G. J. Riely (2013)
J Natl Compr Canc Netw 11, 161-169
   Abstract »    Full Text »    PDF »
Pertuzumab: new hope for patients with HER2-positive breast cancer.
M. Capelan, L. Pugliano, E. De Azambuja, I. Bozovic, K. S. Saini, C. Sotiriou, S. Loi, and M. J. Piccart-Gebhart (2013)
Ann. Onc. 24, 273-282
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Dual Blockade of HER2 in HER2-Overexpressing Tumor Cells Does Not Completely Eliminate HER3 Function.
J. T. Garrett, C. R. Sutton, M. G. Kuba, R. S. Cook, and C. L. Arteaga (2013)
Clin. Cancer Res. 19, 610-619
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The Role of MET Receptor Tyrosine Kinase in Non-Small Cell Lung Cancer and Clinical Development of Targeted Anti-MET Agents.
K. W. Robinson and A. B. Sandler (2013)
Oncologist 18, 115-122
   Abstract »    Full Text »    PDF »
Dual Targeting of EGFR and HER3 with MEHD7945A Overcomes Acquired Resistance to EGFR Inhibitors and Radiation.
S. Huang, C. Li, E. A. Armstrong, C. R. Peet, J. Saker, L. C. Amler, M. X. Sliwkowski, and P. M. Harari (2013)
Cancer Res. 73, 824-833
   Abstract »    Full Text »    PDF »
Resistance to Irreversible EGF Receptor Tyrosine Kinase Inhibitors through a Multistep Mechanism Involving the IGF1R Pathway.
A. B. Cortot, C. E. Repellin, T. Shimamura, M. Capelletti, K. Zejnullahu, D. Ercan, J. G. Christensen, K.-K. Wong, N. S. Gray, and P. A. Janne (2013)
Cancer Res. 73, 834-843
   Abstract »    Full Text »    PDF »

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