neonatal lethality in knockout mice expressing the kinase-dead form of the gefitinib target gak is caused by pulmonary dysfunction新生儿杀伤力基因敲除小鼠表达的kinase-dead形式gak吉非替尼的目标是由肺功能障碍引起的.pdfVIP

Neonatal Lethality in Knockout Mice Expressing the Kinase-Dead Form of the Gefitinib Target GAK Is Caused by Pulmonary Dysfunction 1. 1. 2 1 1 1 Hiroe Tabara , Yoko Naito , Akihiko Ito , Asako Katsuma , Minami A. Sakurai , Shouichi Ohno , 1 1 1 Hiroyuki Shimizu , Norikazu Yabuta , Hiroshi Nojima * 1 Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan, 2 Department of Pathology, Kinki University Faculty of Medicine, Osaka, Japan Abstract 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