In the present study, we sought to examine the functional significance of the PTPRK–CD133 axis in colon cancer progression and found for the first time that PTPRK‐mediated dephosphorylation of CD133 suppresses the progression of colon cancer cells and also improves their anti‐cancer drug sensitivity at least in part through down‐regulation of pro‐oncogenic CD133–AKT pathway. This evidence concerns the gene PROM1 and colonic neoplasm.