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

Fenton, TR and Nathanson, D and de Albuquerque, C Ponte and Kuga, D and Iwanami, A and Dang, J and Yang, H and Tanaka, K and Oba-Shinjo, SM and Uno, M and Inda, MM and Wykosky, J and Bachoo, RM and James, CD and DePinho, RA and Vandenberg, SR and Zhou, H and Marie, SK and Mischel, PS and Cavenee, WK and 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, 109 (35). 14164 - 14169. ISSN 0027-8424. (doi:https://doi.org/10.1073/pnas.1211962109) (Full text available)

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http://dx.doi.org/10.1073/pnas.1211962109

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 show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Item Type: Article
Additional information: PMCID: PMC3435194
Uncontrolled keywords: Animals, Astrocytes, Brain Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Disease Models, Animal, Drug Resistance, Neoplasm, Glioblastoma, Humans, Mice, Mice, Mutant Strains, Mice, Nude, PTEN Phosphohydrolase, Phosphorylation, Protein Kinase Inhibitors, Quinazolines, Receptor, Epidermal Growth Factor, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured, Tyrosine
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Tim Fenton
Date Deposited: 23 May 2017 16:46 UTC
Last Modified: 08 Jun 2017 08:53 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/61514 (The current URI for this page, for reference purposes)
Fenton, TR: https://orcid.org/0000-0002-4737-8233
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