The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma
The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma
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第三代EGFR抑制剂AZD9291通过持续阻断胶质母细胞瘤中的ERK信号传导克服原发性耐药
DOI：
10.1186/s13046-019-1235-7
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发表时间：
2019-05-23
影响因子：
11.3
通讯作者：
Yu, Rutong
中科院分区：
文献类型：
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作者：
Liu, Xuejiao;Chen, Xiangyu;Yu, Rutong
背景胶质母细胞瘤（GBM）是一种致死性脑肿瘤，目前缺乏有效的治疗方法。表皮生长因子受体（EGFR）被认为是GBM治疗的一个有吸引力的靶点。然而，GBM对第一代和第二代EGFR抑制剂的反应非常差。第三代EGFR靶向药物AZD 9291是一种新型的不可逆抑制剂。值得注意的是，AZD 9291具有良好的血脑屏障穿透能力，具有治疗脑肿瘤的潜力。MethodsIn this study，我们在临床前GBM模型中评价了AZD 9291的抗肿瘤活性和有效性。重要的是，AZD 9291抑制GBM细胞增殖的效率比第一代EGFR抑制剂高10倍以上。AZD 9291诱导GBM细胞周期阻滞，并显著抑制GBM细胞的集落形成、迁移和侵袭。在原位GBM模型中，AZD 9291治疗显著抑制肿瘤存活并延长动物存活。AZD 9291的潜在抗GBM机制与第一代EGFR抑制剂不同。结论AZD 9291对GBM细胞的EGFR/ERK信号通路具有较好的抑制作用，且在体内外均具有良好的临床前活性，AZD 9291已被批准用于肺癌的治疗，且安全性和耐受性良好。我们的结果支持使用AZD 9291进行抗GBM治疗的临床试验的可能性。
BackgroundGlioblastoma (GBM) is a fatal brain tumor, lacking effective treatment. Epidermal growth factor receptor (EGFR) is recognized as an attractive target for GBM treatment. However, GBMs have very poor responses to the first- and second-generation EGFR inhibitors. The third-generation EGFR-targeted drug, AZD9291, is a novel and irreversible inhibitor. It is noteworthy that AZD9291 shows excellent blood–brain barrier penetration and has potential for the treatment of brain tumors.MethodsIn this study, we evaluated the anti-tumor activity and effectiveness of AZD9291 in a preclinical GBM model.ResultsAZD9291 showed dose-responsive growth inhibitory activity against six GBM cell lines. Importantly, AZD9291 inhibited GBM cell proliferation > 10 times more efficiently than the first-generation EGFR inhibitors. AZD9291 induced GBM cell cycle arrest and significantly inhibited colony formation, migration, and invasion of GBM cells. In an orthotopic GBM model, AZD9291 treatment significantly inhibited tumor survival and prolonged animal survival. The underlying anti-GBM mechanism of AZD9291 was shown to be different from that of the first-generation EGFR inhibitors. In contrast to erlotinib, AZD9291 continuously and efficiently inhibited the EGFR/ERK signaling in GBM cells.ConclusionAZD9291 demonstrated an efficient preclinical activity in GBM in vitro and in vivo models.AZD9291 has been approved for the treatment of lung cancer with good safety and tolerability. Our results support the possibility of conducting clinical trials of anti-GBM therapy using AZD9291.