Taking advantage of our previous findings where activation of the NRF2 pathway by high glucose or curcumin compounds reduces cancer cell sensitivity to anticancer agents in parallel with impairment of the p53 activity [15,22,23,24,25], the aim of this study was to investigate the cell response to chemotherapeutic drugs, with regard to p53 activity, by generating NRF2-null colon cancer cells with the CRISPR-Cas9 technology. This evidence concerns the gene TP53 and malignant colon neoplasm.