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, Sueli Mieko 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*Frank B. Furnari

*Corresponding author for this work

Research output: Contribution to journalArticle

74 Scopus citations

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

Keywords

  • Erlotinib
  • Gefitinib
  • Glioma
  • Phosphatase

ASJC Scopus subject areas

  • General

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    Fenton, T. R., Nathanson, D., Ponte De Albuquerque, C., Kuga, D., Iwanami, A., Dang, J., Yang, H., Tanaka, K., Oba-Shinjo, S. M., Uno, M., Del Mar Inda, M., Wykosky, J., Bachoo, R. M., James, C. D., DePinho, R. A., Vandenberg, S. R., Zhou, H., Marie, S. K. N., Mischel, P. S., ... Furnari, F. B. (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, 109(35), 14164-14169. https://doi.org/10.1073/pnas.1211962109