Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240.
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.
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
Tim R
TR
Fenton
David
D
Nathanson
Claudio
C
Ponte de Albuquerque
Daisuke
D
Kuga
Akio
A
Iwanami
Julie
J
Dang
Huijun
H
Yang
Kazuhiro
K
Tanaka
Sueli Mieko
SM
Oba-Shinjo
Miyuki
M
Uno
Maria del Mar
MM
Inda
Jill
J
Wykosky
Robert M
RM
Bachoo
C David
CD
James
Ronald A
RA
DePinho
Scott R
SR
Vandenberg
Huilin
H
Zhou
Suely K N
SK
Marie
Paul S
PS
Mischel
Webster K
WK
Cavenee
Frank B
FB
Furnari
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014443:Tyrosine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse