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Submitted on June 18, 2004
Accepted on July 19, 2004
Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways
Raffaella Sordella 1, Daphne W. Bell 1, Daniel A. Haber 1, Jeffrey Settleman 1*
1 Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Bldg 149, 13th Street, Charlestown, MA 02129, USA.
* To whom correspondence should be addressed.
Jeffrey Settleman , E-mail: settleman{at}helix.mgh.harvard.edu
Gefitinib (Iressa) is a tyrosine kinase inhibitor that targetsthe epidermal growth factor receptor (EGFR), and induces dramaticclinical responses in non-small cell lung cancers (NSCLCs) withactivating mutations within the EGFR kinase domain. We reportthat these mutant EGFRs selectively activate Akt and STAT signalingpathways, which promote cell survival, but have no effect onErk/MAPK signaling, which induces proliferation. NSCLC cellsexpressing mutant EGFRs underwent extensive apoptosis followingsiRNA-mediated knockdown of the mutant EGFR or treatment withpharmacological inhibitors of Akt and STAT signaling, and wererelatively resistant to apoptosis induced by conventional chemotherapeuticdrugs. Thus, mutant EGFRs selectively transduce survival signalson which NSCLCs become dependent; inhibition of those signalsby Gefitinib may contribute to the drug's efficacy.
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Transcriptional Profiling Identifies Cyclin D1 as a Critical Downstream Effector of Mutant Epidermal Growth Factor Receptor Signaling.
S. Kobayashi, T. Shimamura, S. Monti, U. Steidl, C. J. Hetherington, A. M. Lowell, T. Golub, M. Meyerson, D. G. Tenen, G. I. Shapiro, et al. (2006)
Cancer Res.
66, 11389-11398
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Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non-Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels.
B. A. Helfrich, D. Raben, M. Varella-Garcia, D. Gustafson, D. C. Chan, L. Bemis, C. Coldren, A. Baron, C. Zeng, W. A. Franklin, et al. (2006)
Clin. Cancer Res.
12, 7117-7125
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Molecular Mechanisms of RET Receptor-Mediated Oncogenesis in Multiple Endocrine Neoplasia 2B..
T. S. Gujral, V. K. Singh, Z. Jia, and L. M. Mulligan (2006)
Cancer Res.
66, 10741-10749
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Tumorigenic Conversion of Primary Human Esophageal Epithelial Cells Using Oncogene Combinations in the Absence of Exogenous Ras.
S.-H. Kim, H. Nakagawa, A. Navaraj, Y. Naomoto, A. J.P. Klein-Szanto, A. K. Rustgi, and W. S. El-Deiry (2006)
Cancer Res.
66, 10415-10424
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Potentiation of the Effect of Erlotinib by Genistein in Pancreatic Cancer: The Role of Akt and Nuclear Factor-{kappa}B.
B. F. El-Rayes, S. Ali, I. F. Ali, P. A. Philip, J. Abbruzzese, and F. H. Sarkar (2006)
Cancer Res.
66, 10553-10559
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The p110{alpha} isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation.
J. J. Zhao, H. Cheng, S. Jia, L. Wang, O. V. Gjoerup, A. Mikami, and T. M. Roberts (2006)
PNAS
103, 16296-16300
|Abstract »|Full Text »|PDF »
Advances in Chemotherapy of Non-small Cell Lung Cancer..
Non-Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation.
A. K. Das, M. Sato, M. D. Story, M. Peyton, R. Graves, S. Redpath, L. Girard, A. F. Gazdar, J. W. Shay, J. D. Minna, et al. (2006)
Cancer Res.
66, 9601-9608
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Pyridone 6, A Pan-Janus-Activated Kinase Inhibitor, Induces Growth Inhibition of Multiple Myeloma Cells.
L. Pedranzini, T. Dechow, M. Berishaj, R. Comenzo, P. Zhou, J. Azare, W. Bornmann, and J. Bromberg (2006)
Cancer Res.
66, 9714-9721
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Modulation of Signal Transducer and Activator of Transcription 5b Activity in Breast Cancer Cells by Mutation of Tyrosines within the Transactivation Domain.
Epidermal Growth Factor Receptor as a Therapeutic Target in Human Thyroid Carcinoma: Mutational and Functional Analysis.
C. S. Mitsiades, V. Kotoula, V. Poulaki, E. Sozopoulos, J. Negri, E. Charalambous, G. Fanourakis, G. Voutsinas, S. Tseleni-Balafouta, and N. Mitsiades (2006)
J. Clin. Endocrinol. Metab.
91, 3662-3666
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Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib.
K. D. Carey, A. J. Garton, M. S. Romero, J. Kahler, S. Thomson, S. Ross, F. Park, J. D. Haley, N. Gibson, and M. X. Sliwkowski (2006)
Cancer Res.
66, 8163-8171
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Different Responses to Gefitinib in Lung Adenocarcinoma Coexpressing Mutant- and Wild-Type Epidermal Growth Factor Receptor Genes.
W.-C. Chou, S.-F. Huang, K.-Y. Yeh, H.-M. Wang, M.-Y. Liu, J.-J. Hsieh, Y.-C. Cheung, and J. W.-C. Chang (2006)
Jpn. J. Clin. Oncol.
36, 523-526
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Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity..
E. Buck, A. Eyzaguirre, J. D. Haley, N. W. Gibson, P. Cagnoni, and K. K. Iwata (2006)
Mol. Cancer Ther.
5, 2051-2059
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Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non-Small Cell Lung Cancer Cell Lines.
C. D. Coldren, B. A. Helfrich, S. E. Witta, M. Sugita, R. Lapadat, C. Zeng, A. Baron, W. A. Franklin, F. R. Hirsch, M. W. Geraci, et al. (2006)
Mol. Cancer Res.
4, 521-528
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Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas..
E. L. Kwak, J. Jankowski, S. P. Thayer, G. Y. Lauwers, B. W. Brannigan, P. L. Harris, R. A. Okimoto, S. M. Haserlat, D. R. Driscoll, D. Ferry, et al. (2006)
Clin. Cancer Res.
12, 4283-4287
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Genomic approaches to lung cancer..
R. K. Thomas, B. Weir, and M. Meyerson (2006)
Clin. Cancer Res.
12, 4384s-4391s
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Epidermal growth factor receptor mutation testing in the care of lung cancer patients..
L. V. Sequist, V. A. Joshi, P. A. Janne, D. W. Bell, P. Fidias, N. I. Lindeman, D. N. Louis, J. C. Lee, E. J. Mark, J. Longtine, et al. (2006)
Clin. Cancer Res.
12, 4403s-4408s
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Targeted therapies in combination with chemotherapy in non-small cell lung cancer..
