Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals.
Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Our clinical data showed NSCLC patients with exon 19 deletions survived longer following gefitinib treatment than those with exon 21 point mutations. We aimed to investigate whether these two mutations produced differences in phosphorylation of EGFR and downstream signals. Two stable cell lines expressing these mutations were obtained by transfection. Inhibition of phosphorylation of EGFR, Akt, and Erk by gefitinib was detected using Western blotting, and cell inhibition tests were conducted to evaluate the bio-behavior. Gefitinib inhibited the phosphorylation of EGFR, Akt, and Erk to a greater degree in exon 19 deletion cells than in L858R cells. Gefitinib produced G1 arrest in more of the cells with exon 19 deletion than with L858R. This might be attributable to patient selection in TKIs therapy.
Zhu
Jian-quan
JQ
Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Zhong
Wen-zhao
WZ
Zhang
Guo-chun
GC
Li
Rong
R
Zhang
Xu-chao
XC
Guo
Ai-lin
AL
Zhang
Yi-fang
YF
An
She-juan
SJ
Mok
Tony S
TS
Wu
Yi-long
YL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005091:Exons; D005260:Female; D000077156:Gefitinib; D018773:Genes, erbB-1; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077156:Gefitinib