Aurora Kinases as Therapeutic Targets in Multiple Myeloma.

BACKGROUND: We have previously found that in multiple myeloma there is amplification of the centrosome, the organelle that nucleates the mitotic spindle. We have reported that RHAMM is a component of the centrosome which interacts with TPX2, the protein that targets Aurora A kinase to the mitotic spindle. We have also shown that RHAMM expression and alternative splicing in myeloma correlate with centrosome amplification, aggressive disease and poor survival. These findings led us to speculate that Aurora A and possibly other Aurora kinases are potential therapeutic targets in myeloma.

METHODS: We examined the expression of Aurora A, B and C kinases in 5 myeloma cell lines and autoMACS-purified CD138+ myeloma bone marrow plasma cells from 20 patients. We assessed the anti-proliferative and pro-apoptotic effects of Aurora A knockdown in myeloma cell lines with RNA interference. We investigated the anti-myeloma activity of two potent, selective Aurora kinase inhibitors, VE-465 (Merck/Vertex) and AZD1152 (AstraZeneca), in 5 myeloma cell lines, in CD138+ bone marrow plasma cells from 2 myeloma patients, and in a NOD/SCID murine xenograft model.

RESULTS: Aurora A, B and C kinases are ubiquitously expressed in both myeloma cell lines and myeloma bone marrow plasma cells. Expression levels vary among patients. Aurora A and B are expressed in myeloma plasma cells at levels comparable to that seen in the CD138- cells from the same marrow sample, and comparable to the levels seen in normal marrow from control individuals. Aurora C, while expressed at low levels, is consistently ectopically overexpressed in myeloma plasma cells relative to coexisting CD138- cells and normal marrow. In myeloma cell lines, Aurora A knockdown with RNA interference induces apoptosis and cell killing. In all five myeloma cell lines tested, and in myeloma bone marrow plasma cells from two patients, both VE-465 and AZD1152 induce apoptosis and myeloma cell killing at nanomolar concentrations, to varying degrees (20–80% reduction in cell viability). VE-465 is known to inhibit all three Aurora kinases with comparable specificity, while AZD1152 is known to inhibit Aurora B and C more selectively than Aurora A. Despite these differences in activity, both compounds have comparable pre-clinical efficacy against myeloma. Myeloma cell lines treated with either agent demonstrate a phenotype consistent with target inhibition. Both drugs show additive effects on killing of cell lines and primary myeloma cells when combined with dexamethasone, even in dexamethasone-resistant cells. Anti-myeloma activity was seen with single agent Aurora kinase inhibition in the murine model, at well tolerated doses.

CONCLUSIONS: Aurora kinases are potential therapeutic targets in myeloma. Aurora kinase inhibitors comprise an emerging class of anti-cancer drug therapy that deserves further evaluation for myeloma patients.