Open AccessActivation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib‐resistance in cells carrying EGFR mutation
Author(s) -
Uchida Akiko,
Hirano Seiki,
Kitao Hiroyuki,
Ogino Atsuko,
Rai Kanmei,
Toyooka Shinichi,
Takigawa Nagio,
Tabata Masahiro,
Takata Minoru,
Kiura Katsuyuki,
Tanimoto Mitsune
Publication year - 2007
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00387.x
Subject(s) - gefitinib , epidermal growth factor receptor , cancer research , transfection , protein kinase b , epidermal growth factor , mapk/erk pathway , cyclin dependent kinase 8 , cell culture , tyrosine kinase , hek 293 cells , biology , tyrosine kinase inhibitor , cell growth , growth inhibition , egfr inhibitors , signal transduction , cancer , microbiology and biotechnology , biochemistry , genetics , notch signaling pathway
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. ( Cancer Sci 2007; 98: 357–363)