Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling

Abstract

Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis. In breast cancer cells, DN10764 inhibited cell proliferation and GAS6-mediated AXL signaling, consequently resulting in suppressed migration and invasion. In addition, DN10764 induced caspase 3/7-mediated apoptosis in breast cancer cells and inhibited tube formation of human umbilical vein endothelial cells. Finally, DN10764 significantly suppressed the tumor growth and metastasis of breast cancer cells in in vivo metastasis models. Taken together, these data suggest that therapeutic strategies targeting AXL in combination with systemic therapies could improve responses to anti-cancer therapies and reduce breast cancer recurrence and metastases.

Keywords: AXL; breast cancer; kinase inhibitor; metastasis; signal transduction.