The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants

Shinichi Toyooka, Akiko Uchida, Hisayuki Shigematsu, Junichi Soh, Atsuko Ogino, Minoru Takata, Katsuyuki Kiura, Mamoru Ouchida, Takayuki Kosaka, Motoi Aoe, Tetsuya Mitsudomi, Hiroshi Date

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Abstract

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.

Original languageEnglish
Pages (from-to)321-324
Number of pages4
JournalJournal of Thoracic Oncology
Volume2
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

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Keywords

  • B-RAF
  • Epidermal growth factor receptor
  • Epidermal growth factor receptor-tyrosine kinase inhibitors
  • Gefitinib
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Toyooka, S., Uchida, A., Shigematsu, H., Soh, J., Ogino, A., Takata, M., Kiura, K., Ouchida, M., Kosaka, T., Aoe, M., Mitsudomi, T., & Date, H. (2007). The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants. Journal of Thoracic Oncology, 2(4), 321-324. https://doi.org/10.1097/01.JTO.0000263716.92191.be