The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants.
We previously reported one patient with squamous cell carcinoma of the lung that showed the long-term effect to gefitinib with complete response. In the present report, we examine the epidermal growth factor receptor (EGFR) and K-RAS, HER2, and B-RAF mutations in this patient to find a B-RAF exon11 mutation, resulting in a substitution of valine by phenylalanine at codon 470 (V470F) as a novel type of B-RAF mutation in human cancers. In addition, the fluorescence in situ hybridization analysis for EGFR showed the high polysomy status. B-RAF is a nonreceptor serine/threonine kinase whose kinase domain has a structure similar to other protein kinases, including EGFR members. Of interest, the B-RAF V470F mutation corresponds to a position similar to the EGFR G719X mutation located on the phosphate binding (P)-loop of EGFR that clamps ATP into the catalytic cleft. This observation suggests that gefitinib may have an anti-cancer effect on B-RAF mutant tumors. Indeed, previous reports demonstrated that H1666 cells harboring B-RAF G465V mutations showed sensitivity to gefitinib, inhibiting phosphorylation of ERK1/2. We examined the effect of gefitinib on transient transfectants of the B-RAF mutant, but no drastic inhibition of ERK1/2 phosphorylation that was one of the downstream molecules of B-RAF was induced by gefitinib. In summary, we found a novel B-RAF V470F mutation in lung squamous cell carcinoma that showed response to gefitinib. However, our in vitro investigation did not explain the response observed in this particular patient. Further investigation is necessary to elucidate the mechanism of tumor sensitivity to EGFR tyrosine kinase inhibitors.
Toyooka
Shinichi
S
Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Okayama University, Okayama, Japan. s_toyooka@nigeka2.hospital.okayama-u.ac.jp
Uchida
Akiko
A
Shigematsu
Hisayuki
H
Soh
Junichi
J
Ogino
Atsuko
A
Takata
Minoru
M
Kiura
Katsuyuki
K
Ouchida
Mamoru
M
Kosaka
Takayuki
T
Aoe
Motoi
M
Mitsudomi
Tetsuya
T
Date
Hiroshi
H
D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000235:genetics; D012680:Sensitivity and Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D066246:ErbB Receptors; D000077156:Gefitinib; D048493:Proto-Oncogene Proteins B-raf; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases