In this study, we have demonstrated that the lack of the APC tumour suppressor gene, mutated in 80% of sporadic CRC and in 100% of FAP (reviewed in Armaghany, Wilson, Chu, & Mills, 2012), contributed to the carcinogenic properties of the typhoid toxin, in colonic epithelial cells using both classical monolayer 2D culture and 3D organotypic model, by inhibiting concomitantly two key steps of the DDR: DNA repair and DNA damage‐induced cell cycle arrest. Here, APC is linked to colorectal carcinoma.