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

Research output: Contribution to journalArticlepeer-review

1183 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2012-2024
Number of pages13
JournalNew England Journal of Medicine
Volume353
Issue number19
DOIs
Publication statusPublished - Nov 10 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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