Pulmonary dysfunction as adverse effect is attributed to the inhibition of the novel gefitinib target GAK.

肺功能障碍的不良反应归因于新型吉非替尼靶点 GAK 的抑制。

• 批准号: 24700978
• 负责人: NAITO Yoko
• 金额: $ 2.83万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24700978/
• 关键词: ゲフィチニブ; 腫瘍抑制; 間質性肺炎; GAK; 癌抑制; キナーゼ

The aim of this study is to reveal the mechanism by which gefitinib (iressa), an inhibitor of epithelial growth factor receptor (EGFR), suppress tumor progression and cause pulmonary alveolar dysfunction as adverse effect. We found that gefitinib inhibited GAK kinase activity and inhibition of GAK activity caused dysregulation of EGF-EGFR signaling by aberrant controlling of phosphorylation and endocytosis. We clarified that GAK expression was increased in several cancer and inhibition of GAK suppressed cancer progression by inducing apoptosis. These results may be useful for development of a gefitinib-drived drug which prevent side effect associated with gefitinib therapy and have a more beneficial effect on tumor suppression.

本研究的目的是揭示上皮生长因子受体（EGFR）抑制剂吉非替尼（易瑞沙）抑制肿瘤进展并导致肺泡功能障碍的机制。我们发现，吉非替尼抑制GAK激酶活性，GAK活性的抑制通过异常控制磷酸化和内吞作用引起EGF-EGFR信号转导的失调。我们阐明了GAK表达在几种癌症中增加，抑制GAK通过诱导细胞凋亡抑制癌症进展。这些结果可能有助于开发一种吉非替尼驱动的药物，该药物可以防止与吉非替尼治疗相关的副作用，并且对肿瘤抑制具有更有益的效果。