Issues

Tricker, Xu, and colleagues found that combined treatment with the mutant EGFR–selective inhibitor WZ4002 and the MEK inhibitor trametinib delayed the development of acquired resistance in EGFR inhibitor–naïve and EGFR^T790M-positive lung cancer cells. WZ4002/trametinib treatment prevented ERK1/2 reactivation and increased apoptosis. Combination treatment was also significantly more effective than WZ4002 alone in suppressing tumor regrowth in xenograft models and a genetically engineered mouse model of EGFR^T790M-mutant lung cancer. Although EGFR and ERK inhibition were maintained in the majority of WZ4002/trametinib–resistant tumor nodules, both AKT and S6 were frequently reactivated, and the addition of an mTOR inhibitor restored WZ4002/trametinib sensitivity in vitro and in vivo. These results highlight the potential clinical utility of initial cotargeting of EGFR and MEK to prevent the emergence of acquired resistance in EGFR-mutant lung cancer. For details, please see the article by Tricker, Xu, and colleagues on page 960.