INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma.
Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, DeltaEGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16(INK4a)/p19(Arf) or p53, respectively, with or without ectopic expression of DeltaEGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of DeltaEGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/DeltaEGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/DeltaEGFR(2-7) in glioblastoma patients.
Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital (CHUV), BH19-110, Lausanne 1011, Switzerland.
Yan
Y
Lachat
Annie-Claire
AC
Diserens
Michimasa
M
Nozaki
Hiroyuki
H
Kobayashi
Marie-France
MF
Hamou
Sophie
S
Godard
Nicolas
N
De Tribolet
Monika E
ME
Hegi
D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005910:Glioma / Q000201:enzymology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011799:Quinazolines; D020032:Tyrphostins / Q000494:pharmacology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases