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Published Online April 26, 2007
Science DOI: 10.1126/science.1141478

Reports

Submitted on February 20, 2007
Accepted on April 11, 2007

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

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

1 Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
2 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
3 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan.
4 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
5 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
6 Department of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
8 Pfizer Global Research and Development, Department of Research Pharmacology, La Jolla Labs, 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.
Pasi A. Jänne , E-mail: pjanne{at}partners.org

The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are used clinically for the treatment of lung cancers with EGFR activating mutations, but the tumors invariably develop drug resistance. To investigate resistance mechanisms, we isolated gefitinib-resistant clones from an EGFR mutant lung cancer cell line. The resistant cells displayed amplification of the MET oncogene and maintained activation of ERBB3/PI3K/Akt signaling in the presence of gefitinib. Inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 out of 18 (22%) lung cancer specimens that had become resistant to gefitinib or erlotinib. Because amplified MET activates the ERBB3/PI3K pathway in other tumor cell lines, our results raise the possibility that MET amplification promotes drug resistance in other ERBB-driven cancers.


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