Abstract Resistance mechanisms compromise response to single targeted therapies, favoring the idea that combinatorial strategies are key to circumvent this clinical problem. Combinatorial strategies for cancers driven by oncogenic KRAS based on MEK1/2 or KRASG12C inhibitors have so far incorporated abrogation of KRAS proximal effectors involved in oncogenesis or treatment resistance. However, the antitumor effect is highly determined by compensatory mechanisms specifically arising in certain cell types or tumor subgroups. A potential strategy to find drug combinations spanning a large percentage of mutant KRAS lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. Here, integrating a signature-driven drug repurposing approach and a pairwise pharmacological screen, we identify a synergistic drug combination consisting of multityrosine kinase PKC and MEK1/2 inhibitors. The drug combination functions in a genotype specific manner, elicits a cytotoxic response both in vitro and in vivo models, and in part involves inhibition of AURKB. Furthermore, we show that the KRASG12C inhibitor Sotorasib can replace the MEK inhibitor with similar cellular and molecular results, including antitumor effect in a genetically engineered mouse model of lung cancer driven by KRasG12C. Proteome profiling links dysregulation of MYC expression to the effect of PKC inhibitor-based drug combinations. Furthermore, we demonstrate that MYC overexpression functions as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework to nominate drugs entering combinatorial strategies and unveils novel MEK1/2- and KRASG12C-based therapies for lung cancer.