Non-covalent tyrosine kinase inhibitors bind and inactivate sensitive ligand-responsive EGFR cancer mutants

Stable Identifier
R-HSA-1220610
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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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).

Literature References
PubMed ID Title Journal Year
17349580 Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity

Yun, CH, Boggon, TJ, Li, Y, Woo, MS, Greulich, H, Meyerson, M, Eck, MJ

Cancer Cell 2007
17177598 Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain

Lee, JC, Vivanco, I, Beroukhim, R, Huang, JHY, Feng, WL, DeBiasi, RM, Yoshimoto, K, King, JC, Nghiemphu, P, Yuza, Y, Xu, Q, Greulich, H, Thomas, RK, Paez, JG, Peck, TC, Linhart, DJ, Glatt, KA, Getz, G, Onofrio, R, Ziaugra, L, Levine, RL, Gabriel, S, Kawaguchi, T, O'Neill, K, Khan, H, Liau, LM, Nelson, SF, Rao, PN, Mischel, P, Pieper, RO, Cloughesy, T, Leahy, DJ, Sellers, WR, Sawyers, CL, Meyerson, M, Mellinghoff, IK

PLoS Med 2006
Participants
Participant Of
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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