In-frame deletion in the EGF receptor alters kinase inhibition by gefitinib.

The Biochemical Journal
Kazuko SakaiKazuto Nishio

Abstract

The existence of an in-frame deletion mutant correlates with the sensitivity of lung cancers to EGFR (epidermal growth factor receptor)-targeted tyrosine kinase inhibitors. We reported previously that the in-frame 15-bp deletional mutation (delE746-A750 type deletion) was constitutively active in cells. Kinetic parameters are important for characterizing an enzyme; however, it remains unclear whether the kinetic parameters of deletion mutant EGFR are similar to those of wild-type EGFR. We analysed autophosphorylation in response to ATP and inhibition of gefitinib for deletion mutant EGFR and wild-type EGFR. Kinetic studies, examining autophosphorylation, were carried out using EGFR fractions extracted from 293-pDelta15 and 293-pEGFR cells transfected with deletion mutant EGFR and wild-type EGFR respectively. We demonstrated the difference in activities between unstimulated wild-type (K(m) for ATP=4.0+/-0.3 microM) and mutant EGFR (K(m) for ATP=2.5+/-0.2 microM). There was no difference in K(m) values between EGF-stimulated wild-type EGFR (K(m) for ATP=1.9+/-0.1 microM) and deletion mutant EGFR (K(m) for ATP=2.2+/-0.2 microM). These results suggest that mutant EGFR is active without ligand stimulation. The K(i) value for gefitin...Continue Reading

References

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Oct 9, 2002·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Yoshiko Kawamura-AkiyamaKazuto Nishio
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Dec 24, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kazuko SakaiKazuto Nishio

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Citations

Nov 18, 2011·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Shunsuke OkumuraYoshinobu Ohsaki
Aug 30, 2008·Experimental Cell Research·Sreenath V Sharma, Jeffrey Settleman
May 12, 2015·Applied Immunohistochemistry & Molecular Morphology : AIMM·Tze-Kiong ErWen-Chan Tsai

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