EGFR Mutation and Resistance of Non-Small-Cell Lung Cancer to Gefitinib

doi:10.1056/NEJMoa044238

Volume 352:786-792		February 24, 2005		Number 8

EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib

Susumu Kobayashi, M.D., Ph.D., Titus J. Boggon, Ph.D., Tajhal Dayaram, B.A., Pasi A. Jänne, M.D., Ph.D., Olivier Kocher, M.D., Ph.D., Matthew Meyerson, M.D., Ph.D., Bruce E. Johnson, M.D., Michael J. Eck, M.D., Ph.D., Daniel G. Tenen, M.D., and Balázs Halmos, M.D.

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SUMMARY

Mutations of the epidermal growth factor receptor (EGFR) genehave been identified in specimens from patients with non–small-celllung cancer who have a response to anilinoquinazoline EGFR inhibitors.Despite the dramatic responses to such inhibitors, most patientsultimately have a relapse. The mechanism of the drug resistanceis unknown. Here we report the case of a patient with EGFR-mutant,gefitinib-responsive, advanced non–small-cell lung cancerwho had a relapse after two years of complete remission duringtreatment with gefitinib. The DNA sequence of the EGFR genein his tumor biopsy specimen at relapse revealed the presenceof a second point mutation, resulting in threonine-to-methionineamino acid change at position 790 of EGFR. Structural modelingand biochemical studies showed that this second mutation ledto gefitinib resistance.

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From the Division of Hematology/Oncology (S.K., T.D., D.G.T., B.H.) and the Department of Pathology (O.K.), Beth Israel Deaconess Medical Center, Harvard Medical School; the Departments of Cancer Biology (T.J.B., M.J.E.), Medical Oncology (P.A.J., B.E.J., M.M.), and Pathology (M.M.), Dana–Farber Cancer Institute, Harvard Medical School; the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School (T.J.B., M.J.E.); and the Department of Medicine, Brigham and Women's Hospital, Harvard Medical School (P.A.J., B.E.J.) — all in Boston; and the Ireland Cancer Center, University Hospitals of Cleveland, Case School of Medicine, Cleveland (B.H.).

Address reprint requests to Dr. Tenen at the Harvard Institutes of Medicine, HIM-954, 77 Louis Pasteur Ave., Boston, MA 02215, or at dtenen{at}bidmc.harvard.edu.

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EGFR Mutation and Response of Lung Cancer to Gefitinib
Toyooka S., Kiura K., Mitsudomi T., Kobayashi S., Tenen D. G., Halmos B.
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N Engl J Med 2005; 352:2136, May 19, 2005. Correspondence

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