EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts
EGFR tyrosine kinase inhibition radiosensitizes and induces apoptosis in malignant glioma and childhood ependymoma xenografts
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DOI：
10.1002/ijc.23488
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发表时间：
2008-07-01
影响因子：
6.4
通讯作者：
Vassal, Gilles
中科院分区：
文献类型：
--
作者：
Geoerger, Birgit;Gaspar, Nathalie;Vassal, Gilles
恶性胶质瘤和儿童室管膜瘤的治疗失败率很高。表皮生长因子受体(EGFR)的激活与多种肿瘤的发生和放射抵抗有关，包括脑肿瘤。因此，结合EGFR靶向和放射治疗是一种潜在的有吸引力的治疗选择。我们在两个异种移植模型中评估了酪氨酸激酶抑制剂吉非替尼的抗肿瘤活性和放射增敏潜力：EGFR扩增的胶质瘤和表达EGFR的室管膜瘤，两者都来自原发肿瘤。连续5天给药100 mg/kg时，吉非替尼可使所有治疗组的肿瘤部分消退，EGFR扩增出IGRG88胶质瘤移植瘤。在给予吉非替尼之前增加1Gy射线照射，9个治疗的肿瘤有5个完全消退和4个部分消退，与单独治疗的19天相比，联合治疗的肿瘤生长明显延迟了33天，这表明有额外的抗肿瘤活性。肿瘤消退与吉非替尼抑制AKT和MAPK通路有关。相反，室管膜瘤IGREP83对辐射敏感，但仍对吉非替尼耐药。联合治疗可抑制辐射诱导的MAPK磷酸化，并通过维持辐射诱导的AKT磷酸化而显著诱导细胞死亡。根据两种疗法的时间安排，观察到联合治疗具有更好的抗肿瘤活性的趋势。因此，通过抑制酪氨酸激酶来靶向EGFR似乎是治疗EGFR驱动的胶质瘤的一种很有前途的新方法，特别是与放射治疗相结合。(C)2008年Wiley-Liss，Inc.
Malignant gliomas and childhood ependymomas have a high rate of treatment failure. Epidermal growth factor receptor (EGFR) activation has been implicated in the tumorigenesis and radioresistance of many cancers, including brain tumors. Therefore, combining EGFR targeting with irradiation is a potentially attractive therapeutic option. We evaluated the tyrosine kinase inhibitor gefitinib for its antitumor activity and potential to radio-sensitize in vivo in two xenograft models: an EGFR amplified glioma and an EGFR expressing ependymoma, both derived from primary tumors. When administered at 100 mg/kg for 5 consecutive days, gefitinib-induced partial tumor regression in all treated EGFR amplified IGRG88 glioma xenografts. The addition of 1 Gy of irradiation prior to gefitinib administration resulted in 5 complete and 4 partial regressions for the 9 treated tumors as well as a significant tumor growth delay of 33 days for the combined treatment compared to 19 days for each therapy alone, suggesting additive antitumor activity. Tumor regression was associated with inhibition of AKT and MAPK pathways by gefitinib. In contrast, the ependymoma IGREP83 was sensitive to irradiation, but remained resistant to gefitinib. Combined treatment was associated with inhibition of radiation-induced MAPK phosphorylation and significant induction of apoptotic cell death though radiation-induced AKT phosphorylation was maintained. Depending on the scheduling of both therapies, a trend towards superior antitumor activity was observed with combined treatment. Thus, EGFR targeting through tyrosine kinase inhibition appears to be a promising new approach in the treatment of EGFR-driven glioma, particularly in combination with radiation therapy. (C) 2008 Wiley-Liss, Inc.