Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line

Atsuko Ogino, Hiroyuki Kitao, Seiki Hirano, Akiko Uchida, Masamichi Ishiai, Toshiyuki Kozuki, Nagio Takigawa, Minoru Takata, Katsuyuki Kiura, Mitsune Tanimoto

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140 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7807-7814
Number of pages8
JournalCancer Research
Volume67
Issue number16
DOIs
Publication statusPublished - Aug 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ogino, A., Kitao, H., Hirano, S., Uchida, A., Ishiai, M., Kozuki, T., Takigawa, N., Takata, M., Kiura, K., & Tanimoto, M. (2007). Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line. Cancer Research, 67(16), 7807-7814. https://doi.org/10.1158/0008-5472.CAN-07-0681