Although the existence of synthetic lethality between BRAF and EGFR in Braf-mutated CRC cells would predict the potential therapeutic effect of a combined targeting, we found that CR-CSCs are resistant to the combination of anti-EGFR or anti-HER2 and BRAF inhibitors due to the constitutive activation of the PI3K/AKT pathway. This evidence concerns the gene PIK3CA and colorectal carcinoma.