Neonatal lethality in knockout mice expressing the kinase-dead form of the gefitinib target GAK is caused by pulmonary dysfunction.
Neonatal lethality in knockout mice expressing the kinase-dead form of the gefitinib target GAK is caused by pulmonary dysfunction.
复制标题
DOI：
10.1371/journal.pone.0026034
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nojima H
中科院分区：
文献类型：
--
作者：
Tabara H;Naito Y;Ito A;Katsuma A;Sakurai MA;Ohno S;Shimizu H;Yabuta N;Nojima H
吉非替尼（易瑞沙）是一种表皮生长因子受体（EGFR）抑制剂，在非小细胞肺癌（NSCLC）患者的治疗中显示出有希望的活性。然而，吉非替尼治疗的不良副作用，如呼吸功能障碍，限制了这种靶向策略的治疗益处。目前的结果表明，这种不良反应可归因于对新型吉非替尼靶点GAK（细胞周期蛋白G相关激酶）的抑制，该靶点GAK与EGFR的酪氨酸激酶活性一样被药物有效抑制。表达GAK激酶死亡形式（GAK-kd）的敲除小鼠在出生后30分钟内死亡，主要是由于呼吸功能障碍。免疫组化分析显示，表面活性蛋白A（SP-A）是丰富的肺泡内的GAK-kd+/+小鼠，但不是在GAK-kd-/-幼崽。E-钙粘蛋白和磷酸化EGFR信号也异常，提示存在扁平肺泡细胞与薄连接。这些结果表明，抑制GAK的吉非替尼可能会导致肺泡功能障碍，本研究可能有助于防止与吉非替尼治疗NSCLC患者的副作用。
Gefitinib (Iressa) is an inhibitor of the epidermal growth factor receptor (EGFR) that has shown promising activity in the treatment of patients with non-small cell lung cancer (NSCLC). However, adverse side effects of gefitinib treatment, such as respiratory dysfunction, have limited the therapeutic benefit of this targeting strategy. The present results show that this adverse effect can be attributed to the inhibition of the novel gefitinib target GAK (Cyclin G-associated kinase), which is as potently inhibited by the drug as the tyrosine kinase activity of EGFR. Knockout mice expressing the kinase-dead form of GAK (GAK-kd) died within 30 min after birth primarily due to respiratory dysfunction. Immunohistochemical analysis revealed that surfactant protein A (SP-A) was abundant within alveolar spaces in GAK-kd+/+ mice but not in GAK-kd-/- pups. E-cadherin and phosphorylated EGFR signals were also abnormal, suggesting the presence of flat alveolar cells with thin junctions. These results suggest that inhibition of GAK by gefitinib may cause pulmonary alveolar dysfunction, and the present study may help prevent side effects associated with gefitinib therapy in NSCLC patients.
登录
查看更多内容
吉非替尼诱导的表达突变体EGFR的NSCLC细胞系杀死需要BIM，并且可以通过BH3 Mimetics增强。
影响因子：
15.8
作者：
Cragg MS;Kuroda J;Puthalakath H;Huang DC;Strasser A
通讯作者：
Strasser A
影响因子：
8
作者：
Gazdar, A. F.
通讯作者：
Gazdar, A. F.
影响因子：
11.5
作者：
Sanford, Mark;Scott, Lesley J.
通讯作者：
Scott, Lesley J.
DOI：
10.1083/jcb.200108123
发表时间：
2002-03-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Conner SD;Schmid SL
通讯作者：
Schmid SL
影响因子：
168.9
作者：
Inoue, A;Saijo, Y;Nukiwa, T
通讯作者：
Nukiwa, T