Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain

Jeffrey C. Lee, Igor Vivanco, Rameen Beroukhim, Julie H.Y. Huang, Whei L. Feng, Ralph M. DeBiasi, Koji Yoshimoto, Jennifer C. King, Phioanh Nghiemphu, Yuki Yuza, Qing Xu, Heidi Greulich, Roman K. Thomas, J. Guillermo Paez, Timothy C. Peck, David J. Linhart, Karen A. Glatt, Gad Getz, Robert Onofrio, Liuda ZiaugraRoss L. Levine, Stacey Gabriel, Tomohiro Kawaguchi, Keith O'Neill, Haumith Khan, Linda M. Liau, Stanley F. Nelson, P. Nagesh Rao, Paul Mischel, Russell O. Pieper, Tim Cloughesy, Daniel J. Leahy, William R. Sellers, Charles L. Sawyers, Matthew Meyerson, Ingo K. Mellinghoff

研究成果: ジャーナルへの寄稿記事

205 引用 (Scopus)

抄録

Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

元の言語英語
ページ(範囲)2264-2273
ページ数10
ジャーナルPLoS Medicine
3
発行部数12
DOI
出版物ステータス出版済み - 12 1 2006

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Missense Mutation
Glioblastoma
Epidermal Growth Factor Receptor
Phosphotransferases
erbB-1 Genes
NIH 3T3 Cells
Mutation
Gene Dosage
Tumor Cell Line
Glioma
Protein-Tyrosine Kinases
Homeostasis
Therapeutics
Cell Line

All Science Journal Classification (ASJC) codes

  • Medicine(all)

これを引用

Lee, J. C., Vivanco, I., Beroukhim, R., Huang, J. H. Y., Feng, W. L., DeBiasi, R. M., ... Mellinghoff, I. K. (2006). Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Medicine, 3(12), 2264-2273. https://doi.org/10.1371/journal.pmed.0030485

Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. / Lee, Jeffrey C.; Vivanco, Igor; Beroukhim, Rameen; Huang, Julie H.Y.; Feng, Whei L.; DeBiasi, Ralph M.; Yoshimoto, Koji; King, Jennifer C.; Nghiemphu, Phioanh; Yuza, Yuki; Xu, Qing; Greulich, Heidi; Thomas, Roman K.; Paez, J. Guillermo; Peck, Timothy C.; Linhart, David J.; Glatt, Karen A.; Getz, Gad; Onofrio, Robert; Ziaugra, Liuda; Levine, Ross L.; Gabriel, Stacey; Kawaguchi, Tomohiro; O'Neill, Keith; Khan, Haumith; Liau, Linda M.; Nelson, Stanley F.; Rao, P. Nagesh; Mischel, Paul; Pieper, Russell O.; Cloughesy, Tim; Leahy, Daniel J.; Sellers, William R.; Sawyers, Charles L.; Meyerson, Matthew; Mellinghoff, Ingo K.

:: PLoS Medicine, 巻 3, 番号 12, 01.12.2006, p. 2264-2273.

研究成果: ジャーナルへの寄稿記事

Lee, JC, Vivanco, I, Beroukhim, R, Huang, JHY, Feng, WL, DeBiasi, RM, Yoshimoto, K, King, JC, Nghiemphu, P, Yuza, Y, Xu, Q, Greulich, H, Thomas, RK, Paez, JG, Peck, TC, Linhart, DJ, Glatt, KA, Getz, G, Onofrio, R, Ziaugra, L, Levine, RL, Gabriel, S, Kawaguchi, T, O'Neill, K, Khan, H, Liau, LM, Nelson, SF, Rao, PN, Mischel, P, Pieper, RO, Cloughesy, T, Leahy, DJ, Sellers, WR, Sawyers, CL, Meyerson, M & Mellinghoff, IK 2006, 'Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain', PLoS Medicine, 巻. 3, 番号 12, pp. 2264-2273. https://doi.org/10.1371/journal.pmed.0030485
Lee, Jeffrey C. ; Vivanco, Igor ; Beroukhim, Rameen ; Huang, Julie H.Y. ; Feng, Whei L. ; DeBiasi, Ralph M. ; Yoshimoto, Koji ; King, Jennifer C. ; Nghiemphu, Phioanh ; Yuza, Yuki ; Xu, Qing ; Greulich, Heidi ; Thomas, Roman K. ; Paez, J. Guillermo ; Peck, Timothy C. ; Linhart, David J. ; Glatt, Karen A. ; Getz, Gad ; Onofrio, Robert ; Ziaugra, Liuda ; Levine, Ross L. ; Gabriel, Stacey ; Kawaguchi, Tomohiro ; O'Neill, Keith ; Khan, Haumith ; Liau, Linda M. ; Nelson, Stanley F. ; Rao, P. Nagesh ; Mischel, Paul ; Pieper, Russell O. ; Cloughesy, Tim ; Leahy, Daniel J. ; Sellers, William R. ; Sawyers, Charles L. ; Meyerson, Matthew ; Mellinghoff, Ingo K. / Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. :: PLoS Medicine. 2006 ; 巻 3, 番号 12. pp. 2264-2273.
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title = "Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain",
abstract = "Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6{\%} (18/132) of glioblastomas and 12.5{\%} (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.",
author = "Lee, {Jeffrey C.} and Igor Vivanco and Rameen Beroukhim and Huang, {Julie H.Y.} and Feng, {Whei L.} and DeBiasi, {Ralph M.} and Koji Yoshimoto and King, {Jennifer C.} and Phioanh Nghiemphu and Yuki Yuza and Qing Xu and Heidi Greulich and Thomas, {Roman K.} and Paez, {J. Guillermo} and Peck, {Timothy C.} and Linhart, {David J.} and Glatt, {Karen A.} and Gad Getz and Robert Onofrio and Liuda Ziaugra and Levine, {Ross L.} and Stacey Gabriel and Tomohiro Kawaguchi and Keith O'Neill and Haumith Khan and Liau, {Linda M.} and Nelson, {Stanley F.} and Rao, {P. Nagesh} and Paul Mischel and Pieper, {Russell O.} and Tim Cloughesy and Leahy, {Daniel J.} and Sellers, {William R.} and Sawyers, {Charles L.} and Matthew Meyerson and Mellinghoff, {Ingo K.}",
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T1 - Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain

AU - Lee, Jeffrey C.

AU - Vivanco, Igor

AU - Beroukhim, Rameen

AU - Huang, Julie H.Y.

AU - Feng, Whei L.

AU - DeBiasi, Ralph M.

AU - Yoshimoto, Koji

AU - King, Jennifer C.

AU - Nghiemphu, Phioanh

AU - Yuza, Yuki

AU - Xu, Qing

AU - Greulich, Heidi

AU - Thomas, Roman K.

AU - Paez, J. Guillermo

AU - Peck, Timothy C.

AU - Linhart, David J.

AU - Glatt, Karen A.

AU - Getz, Gad

AU - Onofrio, Robert

AU - Ziaugra, Liuda

AU - Levine, Ross L.

AU - Gabriel, Stacey

AU - Kawaguchi, Tomohiro

AU - O'Neill, Keith

AU - Khan, Haumith

AU - Liau, Linda M.

AU - Nelson, Stanley F.

AU - Rao, P. Nagesh

AU - Mischel, Paul

AU - Pieper, Russell O.

AU - Cloughesy, Tim

AU - Leahy, Daniel J.

AU - Sellers, William R.

AU - Sawyers, Charles L.

AU - Meyerson, Matthew

AU - Mellinghoff, Ingo K.

PY - 2006/12/1

Y1 - 2006/12/1

N2 - Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

AB - Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

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DO - 10.1371/journal.pmed.0030485

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