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Emergence of Epidermal Growth Factor Receptor T790M Mutation during Chronic Exposure to Gefitinib in a Non–Small Cell Lung Cancer Cell Line

¹ Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; ² Department of Immunology and Molecular Genetics, Kawasaki Medical School, Kurashiki, Okayama, Japan; and ³ Department of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Requests for reprints: Katsuyuki Kiura, Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayaka 700-8558, Japan. Phone: 81-86235-7225; E-mail: kkiura{at}md.okayama-u.ac.jp or Minoru Takata, Department of Human Genetics, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Phone: 81-82257-5828; E-mail: minorut{at}hiroshima-u.ac.jp.

The epidermal growth factor receptor (EGFR)–specific tyrosine kinase inhibitor gefitinib may provide dramatic clinical responses in some patients with pulmonary adenocarcinoma carrying activating mutations of the EGFR. However, prolonged administration of gefitinib may eventually induce acquired resistance in such patients. To gain insight into the mechanisms of this phenomenon, we placed PC-9, a cell line derived from pulmonary adenocarcinoma that has a 15-bp deletion in EGFR exon 19, under the continuous selective pressure of low levels of gefitinib without any mutagen, and established a subline that was able to grow in the presence of 2 µmol/L of gefitinib (designated RPC-9). In this cell line, about half of the reverse transcription-PCR products from mutated EGFR also carried an additional mutation (T790M). In keeping with the proposed role of T790M in abrogating gefitinib binding with EGFR, gefitinib-treated RPC-9 hardly displayed any decrease in the constitutive phosphorylation of EGFR, Akt, or Erk1/2 unlike in PC-9 cells. Interestingly, transfection of the EGFR carrying only a 15-bp deletion reversed the resistance to gefitinib in RPC-9 cells. Thus, the balance of expression levels between gefitinib-sensitive or gefitinib-resistant EGFR may govern the response to gefitinib in lung cancer. [Cancer Res 2007;67(16):7807–14]

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				J. A. Engelman and P. A. Janne Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Clin. Cancer Res., May 15, 2008; 14(10): 2895 - 2899. [Abstract] [Full Text] [PDF]