Molecular mechanisms underlying effects of epidermal growth factor receptor inhibition on invasion, proliferation, and angiogenesis in experimental glioma.
OBJECTIVE
Epidermal growth factor receptor (EGFR) signal transduction pathways are implicated in malignant glioma aggressiveness and promote tumor cell invasion, proliferation, and angiogenesis. Nevertheless, response to EGFR tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) has been disappointing in clinical trials. One potential explanation may come from the diversity of molecular alterations seen in gliomas. To validate that hypothesis, we have investigated responses to gefitinib on various tumor parameters in human malignant gliomas that exhibited different molecular alterations.


METHODS
We used a panel of six human malignant gliomas from established xenografts characterized for their genetic (EGFR, PTEN, TP53, and CDKN2A) and molecular (EGFR, PTEN, ERK, and Akt) alterations. Tumors were treated with gefitinib (1 or 10 micromol/L) for prolonged periods (8 or 16 days) in an organotypic brain slice model that allowed quantification of invasion, proliferation, and angiogenesis.


RESULTS
In nontreated tumors, EGFR amplification was associated with profuse tumor cell invasion. After treatment, invasion was inhibited in tumors with EGFR amplification in a dose-dependent manner. Treatment had only antiproliferative effect in two of three tumors with EGFR amplification. Tumors with PTEN loss were resistant to treatment. We did not observe shrinkage of the tumors after treatment. None of the tumors had mutations of the EGFR kinase domain. Gefitinib had similar antiangiogenic effect in all of the tumors.


CONCLUSIONS
Gefitinib reduces cell invasion in EGFR amplified tumors. PTEN loss of expression seems to be a determinant of resistance. Interestingly, inhibition of angiogenesis by gefitinib seems independent on the EGFR genetic status of the tumors.
INSERM Unit 421 Plasticité cérébrale et thérapeutique, Créteil, France. guillamo-js@chu-caen.fr
Jean-Sébastien
JS
Guillamo
Sophie
S
de Boüard
Samuel
S
Valable
Lena
L
Marteau
Pascal
P
Leuraud
Yannick
Y
Marie
Marie-France
MF
Poupon
Jean-Jacques
JJ
Parienti
Eric
E
Raymond
Marc
M
Peschanski
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; D000077156:Gefitinib