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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 2007

Fingerprint

Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Mutation
Squamous Cell Carcinoma
Neoplasms
Phosphorylation
Lung
Protein-Serine-Threonine Kinases
Valine
gefitinib
Fluorescence In Situ Hybridization
Phenylalanine
Codon
Protein-Tyrosine Kinases
Protein Kinases
Phosphotransferases
Adenosine Triphosphate
Phosphates

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
  • Medicine(all)

Cite this

The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants. / Toyooka, Shinichi; Uchida, Akiko; Shigematsu, Hisayuki; Sou, Junichi; Ogino, Atsuko; Takata, Minoru; Kiura, Katsuyuki; Oouchida, Mamoru; Kosaka, Takayuki; Aoe, Motoi; Mitsudomi, Tetsuya; Date, Hiroshi.

In: Journal of Thoracic Oncology, Vol. 2, No. 4, 04.2007, p. 321-324.

Research output: Contribution to journalArticle

Toyooka, S, Uchida, A, Shigematsu, H, Sou, J, Ogino, A, Takata, M, Kiura, K, Oouchida, 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, vol. 2, no. 4, pp. 321-324. https://doi.org/10.1097/01.JTO.0000263716.92191.be
Toyooka, Shinichi ; Uchida, Akiko ; Shigematsu, Hisayuki ; Sou, Junichi ; Ogino, Atsuko ; Takata, Minoru ; Kiura, Katsuyuki ; Oouchida, Mamoru ; Kosaka, Takayuki ; Aoe, Motoi ; Mitsudomi, Tetsuya ; Date, Hiroshi. / The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants. In: Journal of Thoracic Oncology. 2007 ; Vol. 2, No. 4. pp. 321-324.
@article{2e12bf7900804d2e822490ba7b13a5aa,
title = "The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants",
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.",
keywords = "B-RAF, Epidermal growth factor receptor, Epidermal growth factor receptor-tyrosine kinase inhibitors, Gefitinib, Non-small cell lung cancer",
author = "Shinichi Toyooka and Akiko Uchida and Hisayuki Shigematsu and Junichi Sou and Atsuko Ogino and Minoru Takata and Katsuyuki Kiura and Mamoru Oouchida and Takayuki Kosaka and Motoi Aoe and Tetsuya Mitsudomi and Hiroshi Date",
year = "2007",
month = "4",
doi = "10.1097/01.JTO.0000263716.92191.be",
language = "English",
volume = "2",
pages = "321--324",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "4",

}

TY - JOUR

T1 - The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants

AU - Toyooka, Shinichi

AU - Uchida, Akiko

AU - Shigematsu, Hisayuki

AU - Sou, Junichi

AU - Ogino, Atsuko

AU - Takata, Minoru

AU - Kiura, Katsuyuki

AU - Oouchida, Mamoru

AU - Kosaka, Takayuki

AU - Aoe, Motoi

AU - Mitsudomi, Tetsuya

AU - Date, Hiroshi

PY - 2007/4

Y1 - 2007/4

N2 - 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.

AB - 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.

KW - B-RAF

KW - Epidermal growth factor receptor

KW - Epidermal growth factor receptor-tyrosine kinase inhibitors

KW - Gefitinib

KW - Non-small cell lung cancer

UR - http://www.scopus.com/inward/record.url?scp=34247850951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247850951&partnerID=8YFLogxK

U2 - 10.1097/01.JTO.0000263716.92191.be

DO - 10.1097/01.JTO.0000263716.92191.be

M3 - Article

C2 - 17409805

AN - SCOPUS:34247850951

VL - 2

SP - 321

EP - 324

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 4

ER -