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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 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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|Abstract »|Full Text »|PDF »
An overview of the c-MET signaling pathway..
S. L. Organ and M.-S. Tsao (2011)
Therapeutic Advances in Medical Oncology
3, S7-S19
|Abstract »|PDF »
c-MET as a potential therapeutic target and biomarker in cancer..
J. R. Sierra and M.-S. Tsao (2011)
Therapeutic Advances in Medical Oncology
3, S21-S35
|Abstract »|PDF »
In the clinic: ongoing clinical trials evaluating c-MET-inhibiting drugs..
N. Sharma and A. A. Adjei (2011)
Therapeutic Advances in Medical Oncology
3, S37-S50
|Abstract »|PDF »
Future directions in the evaluation of c-MET-driven malignancies..
J. S. de Bono and T. A. Yap (2011)
Therapeutic Advances in Medical Oncology
3, S51-S60
|Abstract »|PDF »
Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer.
B. T. Aftab, I. Dobromilskaya, J. O. Liu, and C. M. Rudin (2011)
Cancer Res.
71, 6764-6772
|Abstract »|Full Text »|PDF »
Activation of the Insulin-like Growth Factor-1 Receptor Induces Resistance to Epidermal Growth Factor Receptor Antagonism in Head and Neck Squamous Carcinoma Cells.
M. J. Jameson, A. D. Beckler, L. E. Taniguchi, A. Allak, L. B. VanWagner, N. G. Lee, W. C. Thomsen, M. A. Hubbard, and C. Y. Thomas (2011)
Mol. Cancer Ther.
10, 2124-2134
|Abstract »|Full Text »|PDF »
The Role of Irreversible HER Family Inhibition in the Treatment of Patients with Non-Small Cell Lung Cancer.
