Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation

Akiko Uchida, Seiki Hirano, Hiroyuki Kitao, Atsuko Ogino, Kanmei Rai, Shinichi Toyooka, Nagio Takigawa, Masahiro Tabata, Minoru Takata, Katsuyuki Kiura, Mitsune Tanimoto

Research output: Contribution to journalArticle

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Abstract

Patients with pulmonary adenocarcinoma carrying the epidermal growth factor receptor (EGFR) mutation tend to display dramatic clinical response to treatment with the EGFR tyrosine kinase inhibitor gefitinib. Unfortunately, in many cases the cancer cells eventually acquire resistance, and this limits the duration of efficacy. To gain insight into these acquired resistance mechanisms, we first prepared HEK293T cell line stably transfected with either wild-type (WT) or mutant (L858R) EGFR, and then expressed oncogenic K-Ras 12V mutant in the latter transfectant. Although 293T cells expressing wild-type EGFR did not show any growth inhibition by gefitinib treatment similarly to the non-transfected cells, the cells expressing the EGFR-L858R were exquisitely sensitive. Consistently, phospho-Akt levels were decreased in response to gefitinib in cells expressing EGFR-L858R but not in cells with EGFR-WT. In contrast, 293T cells expressing both EGFR-L858R and oncogenic K-Ras were able to proliferate even in the presence of high concentration of gefitinib probably by inducing Erk1/2 activation. We also expressed K-Ras 12V in the gefitinib-sensitive pulmonary adenocarcinoma cell line PC-9, which harbors an in-frame deletion in the EGFR gene. The activated K-Ras inhibited the effects of gefitinib treatment on cell growth, cell death induction and levels of phospho-Akt, as well as phospho-Erk. These data indicate that activated Ras could substitute most of the upstream EGFR signal, and are consistent with the hypothesis that mutational activation of targets immediately downstream from the EGFR could induce the secondary resistance to gefitinib in patients with lung cancer carrying EGFR mutation.

Original languageEnglish
Pages (from-to)357-363
Number of pages7
JournalCancer Science
Volume98
Issue number3
DOIs
Publication statusPublished - Mar 2007

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Epidermal Growth Factor Receptor
Mutation
HEK293 Cells
gefitinib
erbB-1 Genes
Cell Line
Growth
Protein-Tyrosine Kinases
Lung Neoplasms
Cell Death
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation. / Uchida, Akiko; Hirano, Seiki; Kitao, Hiroyuki; Ogino, Atsuko; Rai, Kanmei; Toyooka, Shinichi; Takigawa, Nagio; Tabata, Masahiro; Takata, Minoru; Kiura, Katsuyuki; Tanimoto, Mitsune.

In: Cancer Science, Vol. 98, No. 3, 03.2007, p. 357-363.

Research output: Contribution to journalArticle

Uchida, Akiko ; Hirano, Seiki ; Kitao, Hiroyuki ; Ogino, Atsuko ; Rai, Kanmei ; Toyooka, Shinichi ; Takigawa, Nagio ; Tabata, Masahiro ; Takata, Minoru ; Kiura, Katsuyuki ; Tanimoto, Mitsune. / Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation. In: Cancer Science. 2007 ; Vol. 98, No. 3. pp. 357-363.
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