Treatment of KRAS-dependent cell lines with AZD6244 and CYT387 together prevented pSTAT3 and pERK1/2 activation, indicating that combined TBK1/IKKε, JAK, and MEK inhibition suppressed these multiple KRAS-driven pathways (Supplementary Fig. S7E), resulting in significantly greater cell death compared with either inhibitor alone...we next explored this combination in murine KrasLSL-G12D/WT;p53flox/flox (KP) lung cancer , an aggressive model with high levels of pERK1/2. In contrast to treatment with either agent alone, combined CYT387/AZD6244 therapy for established KP tumors resulted in statistically significant tumor regression (−14.4%, P < 0.001 vs. vehicle, t test; Fig. 7F)... the suppression of multiple RAS effector pathways by combination CYT387/AZD6244 treatment not only impairs the viability of KRAS-dependent NSCLC cells in vitro, but also inhibits tumor growth in the treatment-refractory KP lung cancer model.