siRNA targeting against EGFR, a promising candidate for a novel therapeutic application to lung adenocarcinoma.
OBJECTIVE
To understand the molecular pathogenesis of lung cancer and to establish a novel therapeutic application, we examined the genetic alterations in lung cancer, and studied the effects of gefitinib and siRNA-mediated knockdown of EGFR on lung cancer.


METHODS
We analyzed mutations in EGFR, KRAS, TP53, and ERBB2 in 198 surgically resected lung cancer specimens. We then analyzed the effects of gefitinib and siRNA treatment on lung adenocarcinoma cell lines.


RESULTS
Mutations in EGFR were found only in adenocarcinoma (35 of 106 adenocarcinoma), mainly in females (73%). Mutually exclusive mutations of EGFR and KRAS genes were observed. Mutations of EGFR were well associated with a positive response to gefitinib. Cells with EGFR mutations were very sensitive to gefitinib as well as siRNA-mediated knockdown of EGFR, those with KRAS mutations responded poorly, and those without mutations of KRAS and EGFR showed moderate responses to both treatments.


CONCLUSIONS
Our present results imply that (1) mutation analyses of EGFR and KRAS provide valuable information about whether or not to apply treatments targeting against EGFR and the selection of dosage for such treatments, and (2) siRNA-mediated knockdown is effective in lung adenocarcinomas with EGFR mutation, probably in those with resistance to gefitinib by acquired mutation in EGFR.
Yamanaka
Sumitaka
S
Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan.
Gu
Zhaodi
Z
Sato
Masami
M
Fujisaki
Rumi
R
Inomata
Kenichi
K
Sakurada
Akira
A
Inoue
Akira
A
Nukiwa
Toshihiro
T
Kondo
Takashi
T
Horii
Akira
A
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods*; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D000077156:Gefitinib; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human