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.