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

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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

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Glioblastoma
Epidermal Growth Factor Receptor
Glioma
Phosphotransferases
Odds Ratio
Confidence Intervals
erbB-2 Genes
Tumor Suppressor Proteins
Neoplasms
Gene Expression
Mutation
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Mellinghoff, I. K., Wang, M. Y., Vivanco, I., Haas-Kogan, D. A., Zhu, S., Dia, E. Q., ... Mischel, P. S. (2005). Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. New England Journal of Medicine, 353(19), 2012-2024. https://doi.org/10.1056/NEJMoa051918

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

In: New England Journal of Medicine, Vol. 353, No. 19, 10.11.2005, p. 2012-2024.

Research output: Contribution to journalArticle

Mellinghoff, IK, Wang, MY, Vivanco, I, Haas-Kogan, DA, Zhu, S, Dia, EQ, Lu, KV, Yoshimoto, K, Huang, JHY, Chute, DJ, Riggs, BL, Horvath, S, Liau, LM, Cavenee, WK, Nagesh Rao, P, Beroukhim, R, Peck, TC, Lee, JC, Sellers, WR, Stokoe, D, Prados, M, Cloughesy, TF, Sawyers, CL & Mischel, PS 2005, 'Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors', New England Journal of Medicine, vol. 353, no. 19, pp. 2012-2024. https://doi.org/10.1056/NEJMoa051918
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. New England Journal of Medicine. 2005 Nov 10;353(19):2012-2024. https://doi.org/10.1056/NEJMoa051918
Mellinghoff, Ingo K. ; Wang, Maria Y. ; Vivanco, Igor ; Haas-Kogan, Daphne A. ; Zhu, Shaojun ; Dia, Ederlyn Q. ; Lu, Kan V. ; Yoshimoto, Koji ; Huang, Julie H.Y. ; Chute, Dennis J. ; Riggs, Bridget L. ; Horvath, Steve ; Liau, Linda M. ; Cavenee, Webster K. ; Nagesh Rao, P. ; Beroukhim, Rameen ; Peck, Timothy C. ; Lee, Jeffrey C. ; Sellers, William R. ; Stokoe, David ; Prados, Michael ; Cloughesy, Timothy F. ; Sawyers, Charles L. ; Mischel, Paul S. / Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. In: New England Journal of Medicine. 2005 ; Vol. 353, No. 19. pp. 2012-2024.
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T1 - Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors

AU - Mellinghoff, Ingo K.

AU - Wang, Maria Y.

AU - Vivanco, Igor

AU - Haas-Kogan, Daphne A.

AU - Zhu, Shaojun

AU - Dia, Ederlyn Q.

AU - Lu, Kan V.

AU - Yoshimoto, Koji

AU - Huang, Julie H.Y.

AU - Chute, Dennis J.

AU - Riggs, Bridget L.

AU - Horvath, Steve

AU - Liau, Linda M.

AU - Cavenee, Webster K.

AU - Nagesh Rao, P.

AU - Beroukhim, Rameen

AU - Peck, Timothy C.

AU - Lee, Jeffrey C.

AU - Sellers, William R.

AU - Stokoe, David

AU - Prados, Michael

AU - Cloughesy, Timothy F.

AU - Sawyers, Charles L.

AU - Mischel, Paul S.

PY - 2005/11/10

Y1 - 2005/11/10

N2 - 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.

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