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Originally published in Science Express on 26 April 2007
Science 18 May 2007:
Vol. 316. no. 5827, pp. 1039 - 1043
DOI: 10.1126/science.1141478
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Reports

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*

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}partners.org

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Science. ISSN 0036-8075 (print), 1095-9203 (online)