Neonatal lethality in knockout mice expressing the kinase-dead form of the gefitinib target GAK is caused by pulmonary dysfunction.
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.
Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Hiroe
H
Tabara
Yoko
Y
Naito
Akihiko
A
Ito
Asako
A
Katsuma
Minami A
MA
Sakurai
Shouichi
S
Ohno
Hiroyuki
H
Shimizu
Norikazu
N
Yabuta
Hiroshi
H
Nojima
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002585:Cesarean Section; D004622:Embryo, Mammalian / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D008168:Lung / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*
D015820:Cadherins; D011799:Quinazolines; D066246:ErbB Receptors; C534962:GAK protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077156:Gefitinib