Synergistic effects of inhibitors targeting PI3K and Aurora Kinase A in preclinical inflammatory breast cancer models

Abstract

BackgroundInflammatory breast cancer (IBC) is an aggressive clinical subtype of breast cancer often diagnosed in young women. Lymph node and distant metastases are frequently detected at diagnosis of IBC, and improvements in systemic therapies are needed. For IBC that lack hormone or HER2 expression, no targeted therapies are available. Since the phosphatidyl inositol 3 kinase (PI3K) pathway is frequently deregulated in IBC, some studies have tested the pan PI3K inhibitor Buparlisib (BKM120). Although the SUM149 IBC cell line was resistant to Buparlisib, a functional genomic screen showed that silencing of Aurora kinase A (AURKA) sensitized cells to killing by Buparlisib. In this study, we tested whether combination treatments of PI3K and AURKA inhibitors act synergistically to kill IBC cells and tumors. MethodsSUM149 cells were treated with increasing doses of PI3K inhibitor Buparlisib (BKM120) and AURKA inhibitor Alisertib as monotherapies or combination therapies. Effects on target pathways, cytotoxicity, cell cycle, soft agar colony growth and cell migration were analyzed. The individual and combined treatments were also tested in a mammary orthotopic SUM149 tumor xenograft model to measure effects on tumor growth and metastasis ResultsThe SUM149 IBC cell line treated with Buparlisib showed reduced PI3K/AKT activation but no significant skewing of cell cycle progression. Parallel studies of Alisertib treatment showed that AURKA inhibition led to a significant block in G2/M transition in SUM149 cells. In cytotoxicity assays, Buparlisib and Alisertib combination treatments were highly synergistic compared to monotherapy controls. Evidence of synergy between Buparlisib and Alisertib also extended to soft agar colony growth and wound healing motility in SUM149 cells. The combination of Buparlisib and Alisertib also reduced IBC tumor growth in mammary orthotopic xenograft assays and reduced spontaneous metastases development in lung tissue. ConclusionsAlthough SUM149 IBC cells were relatively resistant to killing by the PI3K inhibitor Buparlisib, our study showed that co-targeting the mitotic kinase AURKA with Alisertib synergized to limit IBC cell growth and motility, as well as IBC tumor growth and metastasis.