Inhibiting the MNK-eIF4E-β-catenin axis increases the responsiveness of aggressive breast cancer cells to chemotherapy.

Advanced breast cancer (eg. stage IV) is resistant to chemotherapy. In this work, we identified potentially druggable targets that are critically involved in chemoresistance. We showed that eIF4E is highly phosphorylated at serine 209 in breast cancer patients in response to chemotherapy, which significantly correlated with poorer clinical responses and outcomes. Depletion of eIF4E enhanced the anti-proliferative and pro-apoptotic effects of chemotherapeutic drugs in breast cancer cells. Chemotherapy activated the Wnt/β-catenin signaling in an eIF4E-dependent manner. However, MNK inhibitors prevented chemotherapeutic drug-induced eIF4E phosphorylation and β-catenin activation, which enhanced the breast cancer cell response to chemotherapy in vitro and in vivo. These findings indicate MNK-eIF4E-β-catenin is an activator of the breast cancer cell response to chemotherapy and highlights the therapeutic value of inhibiting MNK to overcome chemoresistance in breast cancer.