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J Am Chem Soc. 2015 May 27;137(20):6456-9. doi: 10.1021/jacs.5b02326. Epub 2015 May 14.

Structural Differences between Wild-Type and Double Mutant EGFR Modulated by Third-Generation Kinase Inhibitors.

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Departments of †Chemistry, ‡Molecular Biophysics and Biochemistry, and §Molecular, Cellular, and Developmental Biology, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States.


Mutations in the EGFR kinase domain are implicated in non-small-cell lung cancer. Of particular interest is the drug-resistant double mutant (L858R/T790M, DM EGFR), which is not inhibited selectively by any approved kinase inhibitor. Here we apply bipartite tetracysteine display to demonstrate that DM and WT EGFR differ in structure outside the kinase domain. The structural difference is located within the cytoplasmic juxtamembrane segment (JM) that links the kinase domain with the extracellular and transmembrane regions and is essential for EGFR activation. We show further that third-generation DM EGFR-selective TKIs alter JM structure via allostery to restore the conformation found when WT EGFR is activated by the growth factors EGF and HB-EGF. This work suggests that the oncogenic activity of DM EGFR may extend beyond kinase activity per se to include kinase-independent activities. As JM structure may provide a biomarker for these kinase-independent functions, these insights could guide the development of allosteric, DM-selective inhibitors.

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