Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors

Ingo K. Mellinghoff, Maria Y. Wang, Igor Vivanco, Daphne A. Haas-Kogan, Shaojun Zhu, Ederlyn Q. Dia, Kan V. Lu, Koji Yoshimoto, Julie H.Y. Huang, Dennis J. Chute, Bridget L. Riggs, Steve Horvath, Linda M. Liau, Webster K. Cavenee, P. Nagesh Rao, Rameen Beroukhim, Timothy C. Peck, Jeffrey C. Lee, William R. Sellers, David StokoeMichael Prados, Timothy F. Cloughesy, Charles L. Sawyers, Paul S. Mischel

研究成果: Contribution to journalArticle査読

1192 被引用数 (Scopus)

抄録

BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 ( Her2/neu ) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

本文言語英語
ページ(範囲)2012-2024
ページ数13
ジャーナルNew England Journal of Medicine
353
19
DOI
出版ステータス出版済み - 11 10 2005
外部発表はい

All Science Journal Classification (ASJC) codes

  • 医学(全般)

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