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ID 11764
Eprint ID
11764
FullText URL
Thumnail K003326.pdf 93.4 KB
Title Alternative
変異型EGFR発現細胞株への活性化EGFR下流シグナル導入によるgefitinib耐性化
Author
Uchida, Akiko
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-Ras12V 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-Ras12V 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.
Keywords
TYROSINE KINASE INHIBITOR
PREVIOUSLY TREATED PATIENTS
LUNG-CANCER
INCREASES SENSITIVITY
ACQUIRED-RESISTANCE
GENE-MUTATIONS
IN-VIVO
ERLOTINIB
PATHWAYS
IRESSA
Note
http://dx.doi.org/10.1111/j.1349-7006.2007.00387.x
Published Date
2007-03-23
Publication Title
Content Type
Thesis or Dissertation
Official Url
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17270025&dopt=Abstract
language
日本語
File Version
none
Refereed
Unknown