Reversible EGFR TKIs Non-covalent tyrosine kinase inhibitors bind and inactivate sensitive ligand-responsive EGFR cancer mutants Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Non-covalent (reversible) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, lapatinib and vandetanib, selectively inhibit EGFR-stimulated tumor cell growth by blocking EGFR mutant autophosphorylation through competitive inhibition of ATP binding to the kinase domain. A number of EGFR kinase domain mutants and extracellular domain point mutants show increased senistivity to non-covalent TKIs compared with the wild-type EGFR. EGFR kinase domain mutants may be resistant to non-covalent TKIs due to primary or secondary mutations in the kinase domain that increase the affinity of the kinase domain for ATP, such as small insertions within exon 20, and substituion of threonine 790 with methionine (T790M). Pubmed17177598 Pubmed17349580 Reactome Database ID Release 431220610 Reactome, http://www.reactome.org ReactomeREACT_115609 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 has a Stoichiometric coefficient of 2 Active dimers of ligand-responsive EGFR mutants Resistant ligand-responsive EGFR mutants Sensitive ligand-responsive EGFR mutants:Non-covalent EGFR TKIs