Receptor‐type protein tyrosine phosphatase κ ( PTPRK ) is considered to be a candidate tumor suppressor. PTPRK dephosphorylates CD 133, which is a stem cell marker; phosphorylated CD 133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT , but the functional significance of this has remained elusive. In this study, we have demonstrated that knockdown of PTPRK potentiates the pro‐oncogenic CD 133– AKT pathway in colon cancer cells. Intriguingly, depletion of PTPRK significantly reduced sensitivity to the anti‐cancer drug oxaliplatin and was accompanied by up‐regulation of phosphorylation of Bad, a downstream target of AKT . Together, our present observations strongly suggest that the CD 133– PTPRK axis plays a pivotal role in the regulation of colon cancer progression as well as drug resistance.