In conclusion, in this study we show that a “vertical” combination strategy simultaneously targeting BRAF and MEK shuts down BRAF inhibitor-induced paradoxical MAPK activation and may result in therapeutic synergism in preclinical models (both cancer cell lines and patient derived CSC and organoids) of RAS-mut NSCLC and PDAC in vitro. The gene discussed is MAP2K7; the disease is non-small cell lung carcinoma.