Altogether, our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying the BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and drugs targeting the ezrin-regulated actin cytoskeleton as a potential therapeutic approach for BRAFV600E-mutated cancers. Here, EZR is linked to cancer.