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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 tyrosinekinase inhibitor that targets the epidermal growth factor receptor(EGFR) and induces dramatic clinical responses in nonsmall celllung cancers (NSCLCs) with activating mutations within the EGFRkinase domain. We report that these mutant EGFRs selectivelyactivate Akt and signal transduction and activator of transcription(STAT) signaling pathways, which promote cell survival, buthave no effect on extracellular signal–regulated kinasesignaling, which induces proliferation. NSCLC cells expressingmutant EGFRs underwent extensive apoptosis after small interferingRNA–mediated knockdown of the mutant EGFR or treatmentwith pharmacological inhibitors of Akt and STAT signaling andwere relatively resistant to apoptosis induced by conventionalchemotherapeutic drugs. Thus, mutant EGFRs selectively transducesurvival signals on which NSCLCs become dependent; inhibitionof 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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|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 »
Conditional Deletion of Pten Causes Bronchiolar Hyperplasia.
V. Dave, S. E. Wert, T. Tanner, A. R. Thitoff, D. E. Loudy, and J. A. Whitsett (2008) 38, 337-345
|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
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Revoking the Privilege: Targeting HER2 in the Central Nervous System.
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
|Abstract »|Full Text »|PDF »
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 »
Signaling networks assembled by oncogenic EGFR and c-Met.
A. Guo, J. Villen, J. Kornhauser, K. A. Lee, M. P. Stokes, K. Rikova, A. Possemato, J. Nardone, G. Innocenti, R. Wetzel, et al. (2008)
PNAS
105, 692-697
|Abstract »|Full Text »|PDF »
SmgGDS Regulates Cell Proliferation, Migration, and NF-{kappa}B Transcriptional Activity in Non-small Cell Lung Carcinoma.
G. W. Tew, E. L. Lorimer, T. J. Berg, H. Zhi, R. Li, and C. L. Williams (2008)
J. Biol. Chem.
283, 963-976
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Oncogene addiction: setting the stage for molecularly targeted cancer therapy.
Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers.
J. F. Doody, Y. Wang, S. N. Patel, C. Joynes, S. P. Lee, J. Gerlak, R. L. Rolser, Y. Li, P. Steiner, R. Bassi, et al. (2007)
Mol. Cancer Ther.
6, 2642-2651
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Epidermal Growth Factor Receptor Mutation Status and Adjuvant Chemotherapy With Uracil-Tegafur for Adenocarcinoma of the Lung.
H. Suehisa, S. Toyooka, K. Hotta, A. Uchida, J. Soh, Y. Fujiwara, K. Matsuo, M. Ouchida, M. Takata, K. Kiura, et al. (2007)
J. Clin. Oncol.
25, 3952-3957
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Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor dependent human lung cancer cells.
A. Edwards, J. Li, P. Atadja, K. Bhalla, and E. B. Haura (2007)
Mol. Cancer Ther.
6, 2515-2524
|Abstract »|Full Text »|PDF »
Epidermal Growth Factor Receptors with Tyrosine Kinase Domain Mutations Exhibit Reduced Cbl Association, Poor Ubiquitylation, and Down-regulation but Are Efficiently Internalized.
D. Padron, M. Sato, J. W. Shay, A. F. Gazdar, J. D. Minna, and M. G. Roth (2007)
Cancer Res.
67, 7695-7702
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Epidermal Growth Factor Receptor Tyrosine Phosphorylation and Signaling Controlled by a Nuclear Receptor Coactivator, Amplified in Breast Cancer 1.
T. Lahusen, M. Fereshteh, A. Oh, A. Wellstein, and A. T. Riegel (2007)
Cancer Res.
67, 7256-7265
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Oncogenic Activity of Epidermal Growth Factor Receptor Kinase Mutant Alleles Is Enhanced by the T790M Drug Resistance Mutation.
N. Godin-Heymann, I. Bryant, M. N. Rivera, L. Ulkus, D. W. Bell, D. J. Riese II, J. Settleman, and D. A. Haber (2007)
Cancer Res.
67, 7319-7326
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Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3.
K.-W. Lee, L. J. Cobb, V. Paharkova-Vatchkova, B. Liu, J. Milbrandt, and P. Cohen (2007)
Carcinogenesis
28, 1653-1658
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Smoking and Lung Cancer: Future Research Directions.
A Novel Epidermal Growth Factor Receptor Inhibitor Promotes Apoptosis in Non-Small Cell Lung Cancer Cells Resistant to Erlotinib.
T. de La Motte Rouge, L. Galluzzi, K. A. Olaussen, Y. Zermati, E. Tasdemir, T. Robert, H. Ripoche, V. Lazar, P. Dessen, F. Harper, et al. (2007)
Cancer Res.
67, 6253-6262
|Abstract »|Full Text »|PDF »
Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization-Positive/Phospho-Akt-Positive or Never Smoker Patients With Advanced Non-Small-Cell Lung Cancer: The ONCOBELL Trial.
F. Cappuzzo, C. Ligorio, P. A. Janne, L. Toschi, E. Rossi, R. Trisolini, D. Paioli, A. J. Holmes, E. Magrini, G. Finocchiaro, et al. (2007)
J. Clin. Oncol.
25, 2248-2255
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