To delve deeper into the specific role of RNF43 mutations in lung cancer and their relevance to therapy response, we provide the first report of marked efficacy of the dabrafenib and trametinib therapeutic combination in a patient with microsatellite-stable (MSS) non-small-cell lung cancer (NSCLC) with BRAFV600 and RNF43 mutations. The gene discussed is RNF43; the disease is non-small cell lung carcinoma.