Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

Tim R. Fenton, David Nathanson, Claudio Ponte De Albuquerque, Daisuke Kuga, Akio Iwanami, Julie Dang, Huijun Yang, Kazuhiro Tanaka, SueliMieko Oba-Shinjo, Miyuki Uno, Maria Del Mar Inda, Jill Wykosky, Robert M. Bachoo, C. David James, Ronald A. DePinho, Scott R. Vandenberg, Huilin Zhou, Suely K N Marie, Paul S. Mischel, Webster K. Cavenee & 1 others Frank B. Furnari

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3′-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings showthat, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Original languageEnglish (US)
Pages (from-to)14164-14169
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number35
DOIs
StatePublished - Aug 28 2012

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Glioblastoma
Epidermal Growth Factor Receptor
Tyrosine
Phosphorylation
Neoplasms
1-Phosphatidylinositol 4-Kinase
Fibroblast Growth Factor Receptors
Chromosomes, Human, Pair 10
Receptor Protein-Tyrosine Kinases
Phosphoric Monoester Hydrolases
Phosphotransferases
Animal Models
Maintenance
Mutation
Survival
Therapeutics

Keywords

  • Erlotinib
  • Gefitinib
  • Glioma
  • Phosphatase

ASJC Scopus subject areas

  • General

Cite this

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. / Fenton, Tim R.; Nathanson, David; Ponte De Albuquerque, Claudio; Kuga, Daisuke; Iwanami, Akio; Dang, Julie; Yang, Huijun; Tanaka, Kazuhiro; Oba-Shinjo, SueliMieko; Uno, Miyuki; Del Mar Inda, Maria; Wykosky, Jill; Bachoo, Robert M.; James, C. David; DePinho, Ronald A.; Vandenberg, Scott R.; Zhou, Huilin; Marie, Suely K N; Mischel, Paul S.; Cavenee, Webster K.; Furnari, Frank B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 35, 28.08.2012, p. 14164-14169.

Research output: Contribution to journalArticle

Fenton, TR, Nathanson, D, Ponte De Albuquerque, C, Kuga, D, Iwanami, A, Dang, J, Yang, H, Tanaka, K, Oba-Shinjo, S, Uno, M, Del Mar Inda, M, Wykosky, J, Bachoo, RM, James, CD, DePinho, RA, Vandenberg, SR, Zhou, H, Marie, SKN, Mischel, PS, Cavenee, WK & Furnari, FB 2012, 'Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 35, pp. 14164-14169. https://doi.org/10.1073/pnas.1211962109
Fenton, Tim R. ; Nathanson, David ; Ponte De Albuquerque, Claudio ; Kuga, Daisuke ; Iwanami, Akio ; Dang, Julie ; Yang, Huijun ; Tanaka, Kazuhiro ; Oba-Shinjo, SueliMieko ; Uno, Miyuki ; Del Mar Inda, Maria ; Wykosky, Jill ; Bachoo, Robert M. ; James, C. David ; DePinho, Ronald A. ; Vandenberg, Scott R. ; Zhou, Huilin ; Marie, Suely K N ; Mischel, Paul S. ; Cavenee, Webster K. ; Furnari, Frank B. / Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 35. pp. 14164-14169.
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abstract = "Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50{\%} of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3′-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings showthat, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.",
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AU - Kuga, Daisuke

AU - Iwanami, Akio

AU - Dang, Julie

AU - Yang, Huijun

AU - Tanaka, Kazuhiro

AU - Oba-Shinjo, SueliMieko

AU - Uno, Miyuki

AU - Del Mar Inda, Maria

AU - Wykosky, Jill

AU - Bachoo, Robert M.

AU - James, C. David

AU - DePinho, Ronald A.

AU - Vandenberg, Scott R.

AU - Zhou, Huilin

AU - Marie, Suely K N

AU - Mischel, Paul S.

AU - Cavenee, Webster K.

AU - Furnari, Frank B.

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N2 - Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3′-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings showthat, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

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