EGFR lung cancer mutants get specialized

In 2004, three groups independently identified mutations in the epidermal growth factor receptor (EGFR, ErbB1) that sensitized nonsmall cell lung cancers (NSCLCs) to the small-molecule EGFR inhibitors erlotinib and gefitinib (1⇓–3). The most commonly occurring mutation, L834R (or L858R in numbering that includes the signal peptide), also leads to increased EGFR signaling. Despite impressive initial responses to the treatment of tumors containing the L834R substitution, patients inevitably developed resistance as a result of secondary mutations in the kinase domain, most frequently represented by modification of the gatekeeper residue (T766M) (4). After nearly a decade of research into the molecular basis by which activating mutations deregulate EGFR signaling, our understanding of these effects is greatly improved but not complete. In PNAS, Red Brewer et al. (5) use recent developments in our knowledge of EGFR activation to investigate how the L834R and L834R/T766M mutants drive aberrant signaling. Their work identifies a clever strategy in which the cancer mutants cooperate with wild-type EGFR and its close homolog, ErbB2, to produce enhanced activity. These results put a fresh spin on targeting EGFR in cancer. The molecular mechanism which underlies EGFR activation involves formation of a unique asymmetric dimer between two kinase domains. In this arrangement, the C-terminal lobe of one kinase (the donor/activator) interacts with the N-terminal lobe of its partner (the acceptor/receiver), resulting in allosteric activation of the acceptor kinase (Fig. 1A) (6). Conformational changes in the acceptor kinase involve movement of the catalytically important αC helix toward the active site, and extension of the activation loop. These changes open a hydrophobic interface in the N-lobe, promoting association with the donor. Formation of the asymmetric dimer is absolutely essential for activation of EGFR, and the receptor fails to signal as a monomer (6). (A) Activation of …