Occupy EGFR

Abstract

Erlotinib and gefitinib inhibit the growth of non-small cell lung cancer tumors that harbor activating epidermal growth factor receptor (EGFR) mutations but are ineffective against EGFR variants found in glioblastoma. New studies by Barkovich and colleagues and Vivanco and colleagues show that these drugs only occupy the active sites of glioblastoma-derived EGFR mutants to a limited extent and fail to inhibit the activated receptor. Other EGFR inhibitors that target distinct receptor conformations are more effective in the treatment of glioblastoma. These studies reveal distinct drug selectivities for different EGFR mutations and show that an analysis of binding-site occupancy should be considered as a biomarker for inhibitor efficacy in targeting EGFR.

Figure 1

Cartoon representation of the active and inactive conformations of the EGFR kinase domain. In the inactive state (right), the key αC helix is displaced, breaking an important salt bridge between a glutamate in αC (red sticks) and a lysine in the ATP-binding site (blue sticks). In the active conformation (left), αC is moved in towards the center of the N-lobe, so that this salt bridge forms to stabilize ATP binding. Type I inhibitors such as gefitinib and erlotinib bind to the active conformation (left), whereas type II inhibitors (such as lapatinib) bind only to the inactive conformation. As reported by Vivanco et al. (2), only type I inhibitors are effective in NSCLC, whereas only type II inhibitors effectively inhibit EGFR variants found in glioblastoma