Faculty of 1000 evaluation for Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity [dataset]

Robert Fecik
2007 F1000 - Post-publication peer review of the biomedical literature   unpublished
Mutations in the EGFR kinase are a cause of non-small cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788 and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with
more » ... both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wildtype enzyme. Significance-Mutations in the EGFR kinase domain occur in approximately 16% of NSCLCs, but at much higher frequencies in selected populations including non-smokers, women, and East Asian patients. The presence of these mutations correlates with response to small-molecule tyrosine kinase inhibitors targeting EGFR. Because the diverse mutations cluster around the catalytic cleft and because differences in inhibitor sensitivity of the mutants have been reported, it is important to understand the effect of the mutations on inhibitor binding at a structural level. The present work provides a structural foundation for understanding the differential inhibitor sensitivities of the L858R and G719S mutants, and will help guide rational application of currently available EGFR inhibitors and development of more potent and perhaps mutation-specific inhibitors.
doi:10.3410/f.1070897.523848 fatcat:cr6djyqjxzfojp6ybodi33leye