e HER family inhibition is a sound one. Those investigators screened a library of compounds to identify agents that inhibited growth of gefitinib-resistant and gefitinib-sensitive cell lines without producing toxicity in mutant KRAS cells at high concentrations. One such compound, WZ4002, is an irreversible inhibitor with chemical properties that favor 100-fold greater binding to the T790M mutant and 100-fold weaker binding to Dovitinib wild-type EGFR than with neratinib and other quinazoline-based EGFR inhibitors. WZ4002 inhibited L858R/T790M EGFR kinase activity more potently than wildtype EGFR protein activity, whereas the opposite was true for neratinib and gefitinib (i.e., they inhibited wild-type EGFR more potently than the L858R/T790M mutant).

the importance of irreversibility was demonstrated by the markedly lesser efficacy of a reversible WZ4002 analog against T790M-mutant cell lines, as well as by the markedly lesser efficacy of the irreversible WZ4002 against cell lines with an EGFR mutation at Cys 797 that prevented covalent interaction of drug and protein. Such findings indicate that the concept of irreversible HER family inhibition is a sound one that may yet provide a solution to the problem of acquired resistance. Preclinical and early clinical data suggest that there is a valid rationale for the development of irreversible HER family TKIs for the treatment of NSCLC. In vitro studies have demonstrated activity of these agents in preclinical models of first-generation EGFR TKI–resistant NSCLC, and several multitargeted HER family TKIs have provided responses in phase I trials in patients withNSCLC.Clinical trials are under order Dovitinib way to evaluate the efficacy of these agents in patients with advanced NSCLC in a variety of settings, both alone and in combination with chemotherapy and in chemotherapy-naive and previously treated patients. Clinical trials of specific patient subgroups (e.g., those with EGFR-activating mutations or a higherEGFRcopy number) are also ongoing to evaluate irreversible HER family TKIs in selected patient populations. In addition, some clinical trials are evaluating these agents compared with reversible EGFR TKIs.

Whereas results of these trials will help determine the potential for the currently available irreversible HER family TKIs in the treatment paradigm for NSCLC, combination therapy and newer preclinical irreversible inhibitors are building upon lessons learned from previous scientific and current clinical data, with a promise to improve upon the ability to treat EGFR TKI resistance. The author would like to acknowledge Lecia Sequist, M.D., M.P.H., for her insightful comments and careful review. This work was supported by supplier Dovitinib Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). The author received no compensation related to the development of the manuscript.