In conclusion, our present results strongly suggest that PTPRK‐mediated dephosphorylation of CD133 plays an essential role in the progression and drug resistance of colon cancer at least in part through down‐regulation of the pro‐oncogenic AKT–Bad pathway, and this regulatory mechanism might provide a clue to develop a novel and promising strategy for the better treatment of colon cancer patients. Here, PTPRK is linked to malignant colon neoplasm.