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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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B. M. Tijink, T. Laeremans, M. Budde, M. S.-v. Walsum, T. Dreier, H. J. de Haard, C. R. Leemans, and G. A.M.S. van Dongen (2008)
Mol. Cancer Ther.
7, 2288-2297
|Abstract »|Full Text »|PDF »
Case 23-2008 -- A 26-Year-Old Man with Back Pain and a Mass in the Lung.
L. V. Sequist, J. E. Settleman, J. B. Ackman, and A. J. Iafrate (2008)
N. Engl. J. Med.
359, 405-414
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Detection of Mutations in EGFR in Circulating Lung-Cancer Cells.
S. Maheswaran, L. V. Sequist, S. Nagrath, L. Ulkus, B. Brannigan, C. V. Collura, E. Inserra, S. Diederichs, A. J. Iafrate, D. W. Bell, et al. (2008)
N. Engl. J. Med.
359, 366-377
|Abstract »|Full Text »|PDF »
Erlotinib in a Patient With Acute Myelogenous Leukemia and Concomitant Non-Small-Cell Lung Cancer.
V. Pitini, C. Arrigo, and G. Altavilla (2008)
J. Clin. Oncol.
26, 3645-3646
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T. Shimamura, D. Li, H. Ji, H. J. Haringsma, E. Liniker, C. L. Borgman, A. M. Lowell, Y. Minami, K. McNamara, S. A. Perera, et al. (2008)
Cancer Res.
68, 5827-5838
|Abstract »|Full Text »|PDF »
Class 1A PI3K regulates vessel integrity during development and tumorigenesis.
T. L. Yuan, H. S. Choi, A. Matsui, C. Benes, E. Lifshits, J. Luo, J. V. Frangioni, and L. C. Cantley (2008)
PNAS
105, 9739-9744
|Abstract »|Full Text »|PDF »
Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis.
L. P. Stabile, M. E. Rothstein, P. Keohavong, J. Jin, J. Yin, S. R. Land, S. Dacic, T. M. Luong, K. J. Kim, A. M. Dulak, et al. (2008)
Mol. Cancer Ther.
7, 1913-1922
|Abstract »|Full Text »|PDF »
MicroRNA miR-199a* Regulates the MET Proto-oncogene and the Downstream Extracellular Signal-regulated Kinase 2 (ERK2).
S. Kim, U. J. Lee, M. N. Kim, E.-J. Lee, J. Y. Kim, M. Y. Lee, S. Choung, Y. J. Kim, and Y.-C. Choi (2008)
J. Biol. Chem.
283, 18158-18166
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Elevated CRAF as a Potential Mechanism of Acquired Resistance to BRAF Inhibition in Melanoma.
C. Montagut, S. V. Sharma, T. Shioda, U. McDermott, M. Ulman, L. E. Ulkus, D. Dias-Santagata, H. Stubbs, D. Y. Lee, A. Singh, et al. (2008)
Cancer Res.
68, 4853-4861
|Abstract »|Full Text »|PDF »
Specific EGFR Mutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non-Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy.
J. C. Montero, R. Rodriguez-Barrueco, A. Ocana, E. Diaz-Rodriguez, A. Esparis-Ogando, and A. Pandiella (2008)
Clin. Cancer Res.
14, 3237-3241
|Abstract »|Full Text »|PDF »
First-Line Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring Somatic EGFR Mutations.
L. V. Sequist, R. G. Martins, D. Spigel, S. M. Grunberg, A. Spira, P. A. Janne, V. A. Joshi, D. McCollum, T. L. Evans, A. Muzikansky, et al. (2008)
J. Clin. Oncol.
26, 2442-2449
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Molecular Selection of Patients for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time.
F. A. Shepherd (2008)
J. Clin. Oncol.
26, 2426-2427
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Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells.
J. N. Contessa, M. S. Bhojani, H. H. Freeze, A. Rehemtulla, and T. S. Lawrence (2008)
Cancer Res.
68, 3803-3809
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Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.
Met and c-Src Cooperate to Compensate for Loss of Epidermal Growth Factor Receptor Kinase Activity in Breast Cancer Cells.
K. L. Mueller, L. A. Hunter, S. P. Ethier, and J. L. Boerner (2008)
Cancer Res.
68, 3314-3322
|Abstract »|Full Text »|PDF »
EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation.
T. Trowe, S. Boukouvala, K. Calkins, R. E. Cutler Jr., R. Fong, R. Funke, S. B. Gendreau, Y. D. Kim, N. Miller, J. R. Woolfrey, et al. (2008)
Clin. Cancer Res.
14, 2465-2475
|Abstract »|Full Text »|PDF »