作者
Egle Avizienyte, Richard A Ward, Andrew P Garner
发表日期
2008/10/15
期刊
Biochemical Journal
卷号
415
期号
2
页码范围
197-206
出版商
Portland Press Ltd.
简介
Recent clinical data indicates that the emergence of mutant drug-resistant kinase alleles may be particularly relevant for targeted kinase inhibitors. In order to explore how different classes of targeted therapies impact upon resistance mutations, we performed EGFR (epidermal-growth-factor receptor) resistance mutation screens with erlotinib, lapatinib and CI-1033. Distinct mutation spectra were generated with each inhibitor and were reflective of their respective mechanisms of action. Lapatinib yielded the widest variety of mutations, whereas mutational variability was lower in the erlotinib and CI-1033 screens. Lapatinib was uniquely sensitive to mutations of residues located deep within the selectivity pocket, whereas mutation of either Gly796 or Cys797 resulted in a dramatic loss of CI-1033 potency. The clinically observed T790M mutation was common to all inhibitors, but occurred with varying frequencies …
学术搜索中的文章
E Avizienyte, RA Ward, AP Garner - Biochemical Journal, 2008