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Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.

Abstract：

: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 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 wild-type enzyme.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

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

doi

10.1016/j.ccr.2006.12.017

subject

Has Abstract

pub_date

2007-03-01 00:00:00

pages

217-27

issue

3

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(07)00028-1

journal_volume

11

pub_type

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