Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer

摘要

KRAS is one of the driver oncogenes in non-small-celllung cancer (NSCLC) but remains refractory to currentmodalities of targeted pathway inhibition, whichinclude inhibiting downstream kinase MEK to circumventKRAS activation. Here, we show that pulsatile,rather than continuous, treatment with MEK inhibitors(MEKis) maintains T cell activation and enables theirproliferation. Two MEKis, selumetinib and trametinib,induce T cell activation with increased CTLA-4expression and, to a lesser extent, PD-1 expressionon T cells in vivo after cyclical pulsatile MEKi treatment.In addition, the pulsatile dosing schedule aloneshows superior anti-tumor effects and delays theemergence of drug resistance. Furthermore, pulsatileMEKi treatment combined with CTLA-4 blockadeprolongs survival in mice bearing tumors with mutantKras. Our results set the foundation and show theimportance of a combinatorial therapeutic strategyusing pulsatile targeted therapy together with immunotherapyto optimally enhance tumor delay and promotelong-term anti-tumor immunity.