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[Cancer Research 65, 7096-7101, August 15, 2005]
© 2005 American Association for Cancer Research

Priority Reports

An Alternative Inhibitor Overcomes Resistance Caused by a Mutation of the Epidermal Growth Factor Receptor

Susumu Kobayashi1, Hongbin Ji2, Yuki Yuza2, Matthew Meyerson2, Kwok-Kin Wong2, Daniel G. Tenen1 and Balázs Halmos1,3

1 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School; 2 Departments of Medical Oncology and Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 3 University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio

Requests for reprints: Daniel G. Tenen, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: 617-667-5561; Fax: 617-667-3299; E-mail: dtenen{at}bidmc.harvard.edu.

Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in non–small cell lung cancer specimens from patients responding to anilinoquinazoline EGFR inhibitors. However, clinical resistance to EGFR inhibitor therapy is commonly observed. Previously, we showed that such resistance can be caused by a second mutation of the EGFR gene, leading to a T790M amino acid change in the EGFR tyrosine kinase domain and also found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, was able to overcome this resistance on the biochemical level. Here, we present the successful establishment of a stable Ba/F3 cell line model system for the study of oncogenic EGFR signaling and the functional consequences of the EGFR T790M resistance mutation. We show the ability of gefitinib to induce growth arrest and apoptosis in cells transfected with wild-type or L858R EGFR, whereas the T790M mutation leads to high-level functional resistance against gefitinib and erlotinib. In addition, CL-387,785 is able to overcome resistance caused by the T790M mutation on a functional level, correlating with effective inhibition of downstream signaling pathways. Similar data was also obtained with the use of the gefitinib-resistant H1975 lung cancer cell line. The systems established by us should prove useful for the large-scale screening of alternative EGFR inhibitor compounds against the T790M or other EGFR mutations. These data also support the notion that clinical investigations of compounds similar to CL-387,785 may be useful as a treatment strategy for patients with resistance to EGFR inhibitor therapy caused by the T790M mutation.




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