Inhibition of doxorubicin-induced HER3-PI3K-AKT signalling enhances apoptosis of ovarian cancer cells.

Resistance to chemotherapy is a serious problem for the successful treatment of ovarian cancer patients but signalling pathways that contribute to this chemoinsensitivity are largely unknown. We demonstrate that the chemotherapeutic drug doxorubicin induces activation of the HER3-PI3K-AKT signalling cascade in ovarian cancer cells. We further show that the induction of this anti-apoptotic signalling pathway is based on upregulated expression of HER3 ligands, their shedding by the metalloprotease ADAM17, and is dependent on the HER2 receptor. The doxorubicin-mediated activation of this important survival cascade can be blocked by the kinase inhibitors lapatinib or erlotinib as well as by the therapeutic monoclonal antibody trastuzumab. Inhibition of the doxorubicin-induced activation of HER3-PI3K-AKT signalling significantly increased apoptosis of ovarian cancer cells. Besides doxorubicin, treatment of cells with cisplatin resulted in activation of the HER3 receptor whereas other chemotherapeutics did not show this effect. The increase in HER3 phosphorylation was detected in well-established ovarian cancer cell lines which originate from patients previously treated with these chemotherapeutic drugs. Based on these results, we postulate that activation of the HER3-PI3K-AKT cascade represents a major mechanism of chemoresistance in ovarian cancer.