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.
Highlights
Gliomas are the most common form of primary brain tumor and correspond to a heterogeneous group of malignancies [1],[2], including the high-grade forms such as the anaplastic oligodendroglioma (AO), the anaplastic astrocytomas (AA) and the glioblastomas (GBM)
The first step consisted in validating the experimental use of our glioma xenograft models (4 derived from AO and 6 derived from GBM)
Large variations in expression levels were observed between the tumor lines and no relationship was found between the expression level of phospho-EGFR and the histological subtype (AO or GBM)
Summary
Gliomas are the most common form of primary brain tumor and correspond to a heterogeneous group of malignancies [1],[2], including the high-grade forms such as the anaplastic oligodendroglioma (AO), the anaplastic astrocytomas (AA) and the glioblastomas (GBM). High-grade gliomas remain fatal: for example, the median survival for AO ranges between 3 and 10 years [3] while it does not exceed 15 months for GBM [4]. Abnormalities on the EGFR and the EGFR-dependent signaling pathways are the most frequently reported in high-grade gliomas and affect all histological classes [6]. They were associated with an unfavorable outcome [7],[8] and have been implicated in the development and aggressiveness of adult and paediatric highgrade gliomas [9,10,11]. EGFR signaling was shown to promote tumor cell proliferation and survival, invasion and angiogenesis [12,13,14] and mediate resistance to treatment, including ionizing radiation in preclinical models [15,16,17]
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