title: Synergistic antitumor effect between gefitinib and fractionated irradiation in anaplastic oligodendrogliomas cannot be predicted by the Egfr signaling activity.
abstract: In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment "gefitinib + radiotherapy" and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4) harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks) and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks). Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an "EGFR-addictive" behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for "EGFR-addictive" tumors. Unfortunately, neither the usual molecular markers (EGFR amplification, PTEN loss) nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.
authors.affiliation: Université de Lorraine, CRAN, UMR 7039, Campus Science, Vandoeuvre-les-Nancy, France. sophie.pinel@univ-lorraine.fr
authors.forename: Sophie
authors.initials: S
authors.lastname: Pinel
authors.forename: Jihane
authors.initials: J
authors.lastname: Mriouah
authors.forename: Marc
authors.initials: M
authors.lastname: Vandamme
authors.forename: Alicia
authors.initials: A
authors.lastname: Chateau
authors.forename: François
authors.initials: F
authors.lastname: Plénat
authors.forename: Eric
authors.initials: E
authors.lastname: Guérin
authors.forename: Luc
authors.initials: L
authors.lastname: Taillandier
authors.forename: Valérie
authors.initials: V
authors.lastname: Bernier-Chastagner
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Merlin
authors.forename: Pascal
authors.initials: P
authors.lastname: Chastagner
mesh_terms: D000818:Animals; D059248:Chemoradiotherapy / Q000379:methods*; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D051379:Mice; D009837:Oligodendroglioma / Q000188:drug therapy* / Q000532:radiotherapy*; D010750:Phosphoproteins / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D010750:Phosphoproteins; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib