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Science 305 (5687): 1163-1167

Copyright © 2004 by the American Association for the Advancement of Science

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

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

Abstract: 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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Establishment of Patient-Derived Non-Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers.
I. Fichtner, J. Rolff, R. Soong, J. Hoffmann, S. Hammer, A. Sommer, M. Becker, and J. Merk (2008)
Clin. Cancer Res. 14, 6456-6468
   Abstract »    Full Text »    PDF »
Laser Capture Microdissection and Protein Microarray Analysis of Human Non-small Cell Lung Cancer: Differential Epidermal Growth Factor Receptor (EGPR) Phosphorylation Events Associated with Mutated EGFR Compared with Wild Type.
A. J. VanMeter, A. S. Rodriguez, E. D. Bowman, J. Jen, C. C. Harris, J. Deng, V. S. Calvert, A. Silvestri, C. Fredolini, V. Chandhoke, et al. (2008)
Mol. Cell. Proteomics 7, 1902-1924
   Abstract »    Full Text »    PDF »
Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.
U. Guha, R. Chaerkady, A. Marimuthu, A. S. Patterson, M. K. Kashyap, H. C. Harsha, M. Sato, J. S. Bader, A. E. Lash, J. D. Minna, et al. (2008)
PNAS 105, 14112-14117
   Abstract »    Full Text »    PDF »
PIK3CA Mutations and Copy Number Gains in Human Lung Cancers.
H. Yamamoto, H. Shigematsu, M. Nomura, W. W. Lockwood, M. Sato, N. Okumura, J. Soh, M. Suzuki, I. I. Wistuba, K. M. Fong, et al. (2008)
Cancer Res. 68, 6913-6921
   Abstract »    Full Text »    PDF »
Gefitinib Induction of In vivo Detectable Signals by Bcl-2/Bcl-xL Modulation of Inositol Trisphosphate Receptor Type 3.
A. Zannetti, F. Iommelli, R. Fonti, A. Papaccioli, J. Sommella, A. Lettieri, G. Pirozzi, R. Bianco, G. Tortora, M. Salvatore, et al. (2008)
Clin. Cancer Res. 14, 5209-5219
   Abstract »    Full Text »    PDF »
Intratumoral Epiregulin Is a Marker of Advanced Disease in Non-Small Cell Lung Cancer Patients and Confers Invasive Properties on EGFR-Mutant Cells.
J. Zhang, K. Iwanaga, K. C. Choi, M. Wislez, M. G. Raso, W. Wei, I. I. Wistuba, and J. M. Kurie (2008)
Cancer Prevention Research 1, 201-207
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Hsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance.
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
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Epidermal Growth Factor-Induced Esophageal Cancer Cell Proliferation Requires Transactivation of {beta}-Adrenoceptors.
X. Liu, W. K. K. Wu, L. Yu, Z. J. Li, J. J. Y. Sung, S. T. Zhang, and C. H. Cho (2008)
J. Pharmacol. Exp. Ther. 326, 69-75
   Abstract »    Full Text »    PDF »
Increased Prevalence of EGFR-Mutant Lung Cancer in Women and in East Asian Populations: Analysis of Estrogen-Related Polymorphisms.
D. W. Bell, B. W. Brannigan, K. Matsuo, D. M. Finkelstein, R. Sordella, J. Settleman, T. Mitsudomi, and D. A. Haber (2008)
Clin. Cancer Res. 14, 4079-4084
   Abstract »    Full Text »    PDF »
EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer.
J. P. Koivunen, C. Mermel, K. Zejnullahu, C. Murphy, E. Lifshits, A. J. Holmes, H. G. Choi, J. Kim, D. Chiang, R. Thomas, et al. (2008)
Clin. Cancer Res. 14, 4275-4283
   Abstract »    Full Text »    PDF »
Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor.
A. J. Gonzales, K. E. Hook, I. W. Althaus, P. A. Ellis, E. Trachet, A. M. Delaney, P. J. Harvey, T. A. Ellis, D. M. Amato, J. M. Nelson, et al. (2008)
Mol. Cancer Ther. 7, 1880-1889
   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
   Abstract »    Full Text »    PDF »
Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.
J. A. Engelman and P. A. Janne (2008)
Clin. Cancer Res. 14, 2895-2899
   Abstract »    Full Text »    PDF »
Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer.
A. Kumar, E. T. Petri, B. Halmos, and T. J. Boggon (2008)
J. Clin. Oncol. 26, 1742-1751
   Abstract »    Full Text »    PDF »
2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition.
D. Zhong, X. Liu, K. Schafer-Hales, A. I. Marcus, F. R. Khuri, S.-Y. Sun, and W. Zhou (2008)
Mol. Cancer Ther. 7, 809-817
   Abstract »    Full Text »    PDF »
Detection of epidermal growth factor receptor gene mutations in cytology specimens from patients with non-small cell lung cancer utilising high-resolution melting amplicon analysis.
G D Smith, B E Chadwick, C Willmore-Payne, and J S Bentz (2008)
J. Clin. Pathol. 61, 487-493
   Abstract »    Full Text »    PDF »
Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations.
M. Peipp, T. Schneider-Merck, M. Dechant, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. H. I. Parren, J. G. J. van de Winkel, and T. Valerius (2008)
J. Immunol. 180, 4338-4345
   Abstract »    Full Text »    PDF »
BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia.
V. Del Gaizo Moore, K. D. Schlis, S. E. Sallan, S. A. Armstrong, and A. Letai (2008)
Blood 111, 2300-2309
   Abstract »    Full Text »    PDF »
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.
C.-H. Yun, K. E. Mengwasser, A. V. Toms, M. S. Woo, H. Greulich, K.-K. Wong, M. Meyerson, and M. J. Eck (2008)
PNAS 105, 2070-2075
   Abstract »    Full Text »    PDF »
Spontaneous Squamous Cell Carcinoma Induced by the Somatic Inactivation of Retinoblastoma and Trp53 Tumor Suppressors.
A. B. Martinez-Cruz, M. Santos, M. F. Lara, C. Segrelles, S. Ruiz, M. Moral, C. Lorz, R. Garcia-Escudero, and J. M. Paramio (2008)
Cancer Res. 68, 683-692
   Abstract »    Full Text »    PDF »
Revoking the Privilege: Targeting HER2 in the Central Nervous System.
J. N. Contessa and D. A. Hamstra (2008)
Mol. Pharmacol. 73, 271-273
   Abstract »    Full Text »    PDF »
Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib.
T. M. Gilmer, L. Cable, K. Alligood, D. Rusnak, G. Spehar, K. T. Gallagher, E. Woldu, H. L. Carter, A. T. Truesdale, L. Shewchuk, et al. (2008)
Cancer Res. 68, 571-579
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Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel.
A. Sawai, S. Chandarlapaty, H. Greulich, M. Gonen, Q. Ye, C. L. Arteaga, W. Sellers, N. Rosen, and D. B. Solit (2008)
Cancer Res. 68, 589-596
   Abstract »    Full Text »    PDF »

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