Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling
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Joon-Suk Park1,*, ChuHee Lee2,*, Hyun-Kyoung Kim3,*, Dayea Kim3, Jung Beom Son3, Eunhwa Ko3, Joong-Heui Cho3, Nam-Doo Kim3, Hong-Yan Nan2, Choong-Yong Kim1, Sukkyoon Yoon3, Sun-Hwa Lee3, Hwan Geun Choi3
1Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
2Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu, South Korea
3New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
*These authors have contributed equally to this work
Sun-Hwa Lee, email: [email protected]
Hwan Geun Choi, email: [email protected]
Keywords: breast cancer, metastasis, AXL, signal transduction, kinase inhibitor
Received: April 25, 2016 Accepted: October 21, 2016 Published: November 04, 2016
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.
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