In this study, we further investigated the molecular mechanism of adaptive resistance to the MEK inhibitor trametinib in KRAS-mutant NSCLC cells and revealed that trametinib-induced multiple receptor tyrosine kinase (RTK) activation plays a key role in adaptive resistance, suggesting that coinhibition of the MEK/RTK pathways via trametinib plus anlotinib administration has potential value in the treatment of KRAS-mutant NSCLC in preclinical and clinical settings. This evidence concerns the gene KRAS and non-small cell lung carcinoma.