Université de Lorraine, CRAN, UMR 7039, Campus Science, Vandoeuvre-les-Nancy, France.
PLoS One. 2013 Jul 18;8(7):e68333. doi: 10.1371/journal.pone.0068333. Print 2013.
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.
在高级别神经胶质瘤中，确定可能从 EGFR 抑制剂中获益的患者仍然是一个挑战，这阻碍了这些药物的应用。我们使用异种移植模型评估了联合治疗“吉非替尼+放疗”的抗肿瘤作用，并旨在确定反应性肿瘤的特征。在 10 种神经胶质瘤模型中分析了参与 EGFR 依赖性信号通路的磷酸化蛋白的表达。我们专注于三种具有高磷酸化 EGFR、磷酸化 AKT 和磷酸化 MEK1 水平的间变性少突胶质细胞瘤（TCG2、TCG3 和 TCG4）模型。这些模型接受吉非替尼（GEF 75mg/kg/天×5 天/周，连续 2 周）和/或分割放疗（RT：5x2Gy/周，连续 2 周）治疗。我们的结果表明，GEF 和/或 RT 诱导了显著的肿瘤生长延迟。然而，只有 TCG3 异种移植对联合 GEF+RT 高度敏感，约 50%的肿瘤被治愈。治疗开始后 5 天的磷酸化蛋白分析表明，在 TCG3 异种移植中，但不在 TCG2 模型中，EGFR 依赖性通路在 GEF 治疗后被抑制。此外，接受 GEF 单药治疗的 TCG3 荷瘤小鼠表现出短暂的有益治疗反应，随后肿瘤迅速复发，并伴有主要的血管重塑。综上所述，我们的数据表明 TCG3 肿瘤存在“EGFR 成瘾”行为。这项研究证实，吉非替尼联合分割放疗可能是治疗具有 EGFR 异常的间变性少突胶质细胞瘤的有效治疗策略，但这种治疗似乎主要对“EGFR 成瘾”肿瘤有益。不幸的是，通常的分子标志物（EGFR 扩增、PTEN 缺失）或磷酸化蛋白的基础过表达都不能用于区分这种反应性肿瘤。在治疗过程中评估 TKI 对 EGFR 依赖性通路的影响可能更相关，需要进一步验证。
