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Originally published in Science Express on 29 July 2004
Science 20 August 2004:
Vol. 305. no. 5687, pp. 1163 - 1167
DOI: 10.1126/science.1101637
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Reports

Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways

Raffaella Sordella, Daphne W. Bell, Daniel A. Haber, Jeffrey Settleman*

Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal–regulated kinase signaling, which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA–mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent; inhibition of those signals by gefitinib may contribute to the drug's efficacy.

Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.

* To whom correspondence should be addressed. E-mail: settleman{at}helix.mgh.harvard.edu

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Pharmacology and Signaling Properties of Epidermal Growth Factor Receptor Isoforms Studied by Bioluminescence Resonance Energy Transfer.
H. H. Schiffer, E. C. Reding, S. R. Fuhs, Q. Lu, F. Piu, S. Wong, P.-L. H. Littler, D. M. Weiner, W. Keefe, P. K. Tan, et al. (2007)
Mol. Pharmacol. 71, 508-518
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Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing..
L. V. Sequist, V. A. Joshi, P. A. Janne, A. Muzikansky, P. Fidias, M. Meyerson, D. A. Haber, R. Kucherlapati, B. E. Johnson, and T. J. Lynch (2007)
Oncologist 12, 90-98
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Epidermal Growth Factor Receptor Activation: How Exon 19 and 21 Mutations Changed Our Understanding of the Pathway.
R. Rosell, M. Taron, N. Reguart, D. Isla, and T. Moran (2006)
Clin. Cancer Res. 12, 7222-7231
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Update on Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer.
G. J. Riely, K. A. Politi, V. A. Miller, and W. Pao (2006)
Clin. Cancer Res. 12, 7232-7241
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Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs.
M. Ono and M. Kuwano (2006)
Clin. Cancer Res. 12, 7242-7251
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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
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Advances in Chemotherapy of Non-small Cell Lung Cancer..
J. R. Molina, A. A. Adjei, and J. R. Jett (2006)
Chest 130, 1211-1219
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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.
A. M. Weaver and C. M. Silva (2006)
Mol. Endocrinol. 20, 2392-2405
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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..
D. H. Johnson (2006)
Clin. Cancer Res. 12, 4451s-4457s
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Immunogenetic Programs for Viral Induction of Mucous Cell Metaplasia.
M. J. Holtzman, J. T. Battaile, and A. C. Patel (2006)
Am. J. Respir. Cell Mol. Biol. 35, 29-39
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