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

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，并且 GAK 活性的抑制通过磷酸化和内吞作用的异常控制导致 EGF-EGFR 信号传导失调。我们阐明，GAK 表达在多种癌症中增加，抑制 GAK 可通过诱导细胞凋亡来抑制癌症进展。这些结果可能有助于开发吉非替尼驱动的药物，该药物可防止与吉非替尼治疗相关的副作用，并对肿瘤抑制产生更有益的作用。

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.