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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(2008). In vitro differential sensitivity of melanomas to phenothiazines is based on the presence of codon 600 BRAF mutation. Molecular Cancer Therapeutics
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(2008). First-Line Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring Somatic EGFR Mutations. JCO
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(2008). High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood
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Jimeno, A., Tan, A. C., Coffa, J., Rajeshkumar, N.V., Kulesza, P., Rubio-Viqueira, B., Wheelhouse, J., Diosdado, B., Messersmith, W. A., Iacobuzio-Donahue, C., Maitra, A., Varella-Garcia, M., Hirsch, F. R., Meijer, G. A., Hidalgo, M.
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D'Addario, G., Rauch, D., Stupp, R., Pless, M., Stahel, R., Mach, N., Jost, L., Widmer, L., Tapia, C., Bihl, M., Mayer, M., Ribi, K., Lerch, S., Bubendorf, L., Betticher, D. C.
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(2008). Systemic Therapy for Biliary Tract Cancers. The Oncologist
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Miller, V. A., Riely, G. J., Zakowski, M. F., Li, A. R., Patel, J. D., Heelan, R. T., Kris, M. G., Sandler, A. B., Carbone, D. P., Tsao, A., Herbst, R. S., Heller, G., Ladanyi, M., Pao, W., Johnson, D. H.
(2008). Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib. JCO
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Jhawer, M., Goel, S., Wilson, A. J., Montagna, C., Ling, Y.-H., Byun, D.-S., Nasser, S., Arango, D., Shin, J., Klampfer, L., Augenlicht, L. H., Soler, R. P., Mariadason, J. M.
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Peipp, M., Schneider-Merck, T., Dechant, M., Beyer, T., Lammerts van Bueren, J. J., Bleeker, W. K., Parren, P. W. H. I., van de Winkel, J. G. J., Valerius, T.
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Yamashita, T., Forgues, M., Wang, W., Kim, J. W., Ye, Q., Jia, H., Budhu, A., Zanetti, K. A., Chen, Y., Qin, L.-X., Tang, Z.-Y., Wang, X. W.
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