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

本研究旨在揭示上皮生长因子受体（EGFR）抑制剂吉非替尼（iressa）抑制肿瘤进展并引起肺泡功能障碍的不良反应机制。我们发现吉非替尼抑制GAK激酶活性，抑制GAK活性通过异常控制磷酸化和内吞作用导致EGF-EGFR信号通路失调。我们阐明了GAK在几种癌症中的表达增加，抑制GAK通过诱导细胞凋亡来抑制癌症的进展。这些结果可能有助于开发吉非替尼驱动的药物，以防止吉非替尼治疗相关的副作用，并对肿瘤抑制有更有益的作用。

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.