Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
Thomas J. Lynch, M.D., Daphne W. Bell, Ph.D., Raffaella Sordella, Ph.D., Sarada Gurubhagavatula, M.D., Ross A. Okimoto, B.S., Brian W. Brannigan, B.A., Patricia L. Harris, M.S., Sara M. Haserlat, B.A., Jeffrey G. Supko, Ph.D., Frank G. Haluska, M.D., Ph.D., David N. Louis, M.D., David C. Christiani, M.D., Jeff Settleman, Ph.D., and Daniel A. Haber, M.D., Ph.D.
Background Most patients with non–small-cell lung cancerhave no response to the tyrosine kinase inhibitor gefitinib,which targets the epidermal growth factor receptor (EGFR). However,about 10 percent of patients have a rapid and often dramaticclinical response. The molecular mechanisms underlying sensitivityto gefitinib are unknown.
Methods We searched for mutations in the EGFR gene in primarytumors from patients with non–small-cell lung cancer whohad a response to gefitinib, those who did not have a response,and those who had not been exposed to gefitinib. The functionalconsequences of identified mutations were evaluated after themutant proteins were expressed in cultured cells.
Results Somatic mutations were identified in the tyrosine kinasedomain of the EGFR gene in eight of nine patients with gefitinib-responsivelung cancer, as compared with none of the seven patients withno response (P<0.001). Mutations were either small, in-framedeletions or amino acid substitutions clustered around the ATP-bindingpocket of the tyrosine kinase domain. Similar mutations weredetected in tumors from 2 of 25 patients with primary non–small-celllung cancer who had not been exposed to gefitinib (8 percent).All mutations were heterozygous, and identical mutations wereobserved in multiple patients, suggesting an additive specificgain of function. In vitro, EGFR mutants demonstrated enhancedtyrosine kinase activity in response to epidermal growth factorand increased sensitivity to inhibition by gefitinib.
Conclusions A subgroup of patients with non–small-celllung cancer have specific mutations in the EGFR gene, whichcorrelate with clinical responsiveness to the tyrosine kinaseinhibitor gefitinib. These mutations lead to increased growthfactor signaling and confer susceptibility to the inhibitor.Screening for such mutations in lung cancers may identify patientswho will have a response to gefitinib.
Source Information
From the Cancer Center (T.J.L., D.W.B., R.S., S.G., R.A.O., B.W.B., P.L.H., S.M.H., J.G.S., F.G.H., D.N.L., D.C.C., J.S., D.A.H.) and the Departments of Medicine (T.J.L., D.W.B., J.G.S., F.G.H., D.C.C., J.S., D.A.H.) and Pathology (D.N.L.), Massachusetts General Hospital and Harvard Medical School; and the Harvard School of Public Health (S.G., D.C.C.) — all in Boston. Drs. Lynch, Bell, and Sordella contributed equally to the article. This article was published at www.nejm.org on April 29, 2004.
Address reprint requests to Dr. Haber at MGH Cancer Center, Bldg. 149, 13th St., Charlestown, MA 02129, or at haber{at}helix.mgh.harvard.edu.
EGFR Mutations and Sensitivity to Gefitinib
Sorscher S. M., Rich J. N., Rasheed B.K. A., Yan H., Rossi G., Marchioni A., Longo L., Haber D. A., Bell D. W., Lynch T. J.
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N Engl J Med 2004;
351:1260-1261, Sep 16, 2004.
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(2009). Biological and Clinical Features in Predicting Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Systematic Review and Meta-analysis. Anticancer Res
29: 2691-2701
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SHUKUYA, T., TAKAHASHI, T., TAMIYA, A., ONO, A., IGAWA, S., NAKAMURA, Y., TSUYA, A., MURAKAMI, H., NAITO, T., KAIRA, K., ENDO, M., YAMAMOTO, N.
(2009). Gefitinib Plus Paclitaxel after Failure of Gefitinib in Non-small Cell Lung Cancer Initially Responding to Gefitinib. Anticancer Res
29: 2747-2751
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PESEK, M., BENESOVA, L., BELSANOVA, B., MUKENSNABL, P., BRUHA, F., MINARIK, M.
(2009). Dominance of EGFR and Insignificant KRAS Mutations in Prediction of Tyrosine-kinase Therapy for NSCLC Patients Stratified by Tumor Subtype and Smoking Status. Anticancer Res
29: 2767-2773
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Karpel-Massler, G., Schmidt, U., Unterberg, A., Halatsch, M.-E.
(2009). Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?. Mol Cancer Res
7: 1000-1012
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Yang, L., Luo, H., Chen, J., Xing, Q., He, L.
(2009). SePreSA: a server for the prediction of populations susceptible to serious adverse drug reactions implementing the methodology of a chemical-protein interactome. Nucleic Acids Res
37: W406-W412
[Abstract][Full Text]
Versele, M., Talloen, W., Rockx, C., Geerts, T., Janssen, B., Lavrijssen, T., King, P., Gohlmann, H. W.H., Page, M., Perera, T.
(2009). Response prediction to a multitargeted kinase inhibitor in cancer cell lines and xenograft tumors using high-content tyrosine peptide arrays with a kinetic readout. Molecular Cancer Therapeutics
8: 1846-1855
[Abstract][Full Text]
Morita, S., Okamoto, I., Kobayashi, K., Yamazaki, K., Asahina, H., Inoue, A., Hagiwara, K., Sunaga, N., Yanagitani, N., Hida, T., Yoshida, K., Hirashima, T., Yasumoto, K., Sugio, K., Mitsudomi, T., Fukuoka, M., Nukiwa, T.
(2009). Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for Non-Small Cell Lung Cancer with EGFR Mutations. Clin. Cancer Res.
15: 4493-4498
[Abstract][Full Text]
Choi, K., Ahn, Y.-H., Gibbons, D. L., Tran, H. T., Creighton, C. J., Girard, L., Minna, J. D., Qin, F. X.-F., Kurie, J. M.
(2009). Distinct Biological Roles for the Notch Ligands Jagged-1 and Jagged-2. J. Biol. Chem.
284: 17766-17774
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Ichihara, E., Ohashi, K., Takigawa, N., Osawa, M., Ogino, A., Tanimoto, M., Kiura, K.
(2009). Effects of Vandetanib on Lung Adenocarcinoma Cells Harboring Epidermal Growth Factor Receptor T790M Mutation In vivo. Cancer Res.
69: 5091-5098
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Brambilla, E., Gazdar, A.
(2009). Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur Respir J
33: 1485-1497
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Rossi, G., Pelosi, G., Graziano, P., Barbareschi, M., Papotti, M.
(2009). Review Article: A Reevaluation of the Clinical Significance of Histological Subtyping of Non--Small-Cell Lung Carcinoma: Diagnostic Algorithms in the Era of Personalized Treatments. INT J SURG PATHOL
17: 206-218
[Abstract]
Kotoula, V., Sozopoulos, E., Litsiou, H., Fanourakis, G., Koletsa, T., Voutsinas, G., Tseleni-Balafouta, S., Mitsiades, C. S, Wellmann, A., Mitsiades, N.
(2009). Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas. Endocr Relat Cancer
16: 565-572
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Hogan, T., Jing Jie Yu, , Williams, H J., Altaha, R., Xiaobing Liang, , Qi He,
(2009). Oncocytic, focally anaplastic, thyroid cancer responding to erlotinib. J Oncol Pharm Pract
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[Abstract]
Bai, H., Mao, L., Wang, h. S., Zhao, J., Yang, L., An, t. T., Wang, X., Duan, c. J., Wu, n. M., Guo, z. Q., Liu, y. X., Liu, h. N., Wang, y. Y., Wang, J.
(2009). Epidermal Growth Factor Receptor Mutations in Plasma DNA Samples Predict Tumor Response in Chinese Patients With Stages IIIB to IV Non-Small-Cell Lung Cancer. JCO
27: 2653-2659
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Sequist, L. V., Engelman, J. A., Lynch, T. J.
(2009). Toward Noninvasive Genomic Screening of Lung Cancer Patients. JCO
27: 2589-2591
[Full Text]
KUSUMOTO, S., SUGIYAMA, T., ANDO, K., HOSAKA, T., ISHIDA, H., SHIRAI, T., YAMAOKA, T., OKUDA, K., HIROSE, T., OHNISHI, T., INOUE, F., KANOME, T., KADOFUKU, T., SAIJO, N., ADACHII, M., OHMORI, T.
(2009). Combination Effect between Bortezomib and Tumor Necrosis Factor {alpha} on Gefitinib-resistant Non-small Cell Lung Cancer Cell Lines. Anticancer Res
29: 2315-2322
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Leung, E. L.-H., Tam, I. Y.-S., Tin, V. P.-C., Chua, D. T.-T., Sihoe, A. D.-L., Cheng, L.-C., Ho, J. C.-M., Chung, L.-P., Wong, M. P.
(2009). Src Promotes Survival and Invasion of Lung Cancers with Epidermal Growth Factor Receptor Abnormalities and Is a Potential Candidate for Molecular-Targeted Therapy. Mol Cancer Res
7: 923-932
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Freeman, D. J., Bush, T., Ogbagabriel, S., Belmontes, B., Juan, T., Plewa, C., Van, G., Johnson, C., Radinsky, R.
(2009). Activity of panitumumab alone or with chemotherapy in non-small cell lung carcinoma cell lines expressing mutant epidermal growth factor receptor. Molecular Cancer Therapeutics
8: 1536-1546
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Herberger, B., Berger, W., Puhalla, H., Schmid, K., Novak, S., Brandstetter, A., Pirker, C., Gruenberger, T., Filipits, M.
(2009). Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells. Molecular Cancer Therapeutics
8: 1547-1556
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Kaye, F. J.
(2009). Mutation-associated fusion cancer genes in solid tumors. Molecular Cancer Therapeutics
8: 1399-1408
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Guillamo, J.-S., de Bouard, S., Valable, S., Marteau, L., Leuraud, P., Marie, Y., Poupon, M.-F., Parienti, J.-J., Raymond, E., Peschanski, M.
(2009). Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma. Clin. Cancer Res.
15: 3697-3704
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Tyner, J. W., Deininger, M. W., Loriaux, M. M., Chang, B. H., Gotlib, J. R., Willis, S. G., Erickson, H., Kovacsovics, T., O'Hare, T., Heinrich, M. C., Druker, B. J.
(2009). RNAi screen for rapid therapeutic target identification in leukemia patients. Proc. Natl. Acad. Sci. USA
106: 8695-8700
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Natale, R. B., Bodkin, D., Govindan, R., Sleckman, B. G., Rizvi, N. A., Capo, A., Germonpre, P., Eberhardt, W. E.E., Stockman, P. K., Kennedy, S. J., Ranson, M.
(2009). Vandetanib Versus Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer: Results From a Two-Part, Double-Blind, Randomized Phase II Study. JCO
27: 2523-2529
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Rickman, O. B., Vohra, P. K., Sanyal, B., Vrana, J. A., Aubry, M.-C., Wigle, D. A., Thomas, C. F. Jr.
(2009). Analysis of ErbB Receptors in Pulmonary Carcinoid Tumors. Clin. Cancer Res.
15: 3315-3324
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Naumov, G. N., Nilsson, M. B., Cascone, T., Briggs, A., Straume, O., Akslen, L. A., Lifshits, E., Byers, L. A., Xu, L., Wu, H.-k., Janne, P., Kobayashi, S., Halmos, B., Tenen, D., Tang, X. M., Engelman, J., Yeap, B., Folkman, J., Johnson, B. E., Heymach, J. V.
(2009). Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance. Clin. Cancer Res.
15: 3484-3494
[Abstract][Full Text]
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