Structural Insights into Hyperactivation ofEGFR Mutants

Structural studies of isolated EGFR kinase domains, as mentioned above, have provided some insight into how EGFR mutations may confer constitutive activation (12). Activation proceeds via the formation of an asymmetric dimer, in which one monomer adopts an open or active confirmation facilitating the induction of the kinase activity of the other partner in the dimer, which adopts a closed confirmation, under basal conditions. It has been suggested that leucines 858 and 861 in the EGFR protein, which are mutated in NSCLC, interact strongly with hydrophobic side-chains in the so-called N-lobe of the kinase domain in the structural model of the inactive EGFR confirmation. Thus, it is likely that the L858R and L861Q mutations that result in replacement with hydrophilic or polar side-chains perturb the hydrophobic interactions and promote a switch to the open or active confirmation, thus rendering the receptor hyperactive. In addition, erlotinib binding is predicted to be incompatible with the closed or inactive EGFR confirmation, which may explain why tumors from NSCLC patients harboring L858Rmissense mutations are more sensitive to gefitinib, in comparison (45,48).

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