Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells

Abstract

The expression of RHAMM and other centrosome-associated genes are known to correlate with the extent of centrosome amplification in multiple myeloma, and with poor prognosis. RHAMM has a significant interaction with TPX2, a protein which regulates the localization and action of Aurora A kinase (AURKA) at the spindle poles. AURKA is known to be a central determinant of centrosome and spindle function and is a target for cancer therapy. Given these observations, we investigated the role of Aurora kinases as therapeutic targets in myeloma. Here we report that AURKA is expressed ubiquitously in myeloma, to varying degrees, in both cell lines and patients' bone marrow plasma cells. siRNA targeting AURKA induces apoptotic cell death in myeloma cell lines. The Aurora kinase inhibitor VE-465 also induces apoptosis and death in myeloma cell lines and primary myeloma plasma cells. The combination of VE-465 and dexamethasone improves cell killing compared with the use of either agent alone, even in cells resistant to the single agents. The phenotype of myeloma cells treated with VE-465 is consistent with published reports on the effects of Aurora kinase inhibition. Aurora kinase inhibitors should be pursued as potential treatments for myeloma.

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

“…However, both kinases have different effects on the mitotic process [18]. Numerous inhibitors have been developed against both classes of kinases and some aurora kinase inhibitors have been shown to have effects on multiple myeloma [25][26][27][28][29][30][31]. Indeed, ENMD-2076 is currently undergoing phase I trial [18].…”

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

“…[15][16][17][18] Because high Aurora-A gene expression has been correlated with centrosome amplification and a worse prognosis in MM, inhibition of Aurora-A may prove to be therapeutically beneficial. 2,6,9,[19][20][21][22][23][24] Recently, we and others have shown that inhibition of Aurora-A kinase gene expression in MM cells by RNAi induces apoptosis Submitted December 18, 2009; accepted March 31, 2010. Prepublished online as Blood First Edition paper, April 9, 2010; DOI 10.1182 DOI 10.…”

“…6,19,24,27,33 A recent analysis showed no association between genetic instability and expression of Aurora kinases in MM. 9,20 In this preclinical study, we investigated the anti-MM activity of MLN8237, an orally available novel small molecule selective inhibitor of Aurora-A kinase. Aurora-A kinase activity is necessary for proper mitotic progression 11,12,26 : expression of Aurora-A kinase protein peaks during mitosis and is activated by phosphorylation at Thr288.…”

“…2,3 Aberrant or overexpression of D-type cyclins is ubiquitous in MM, 4,5 and Aurora kinases regulate cell-cycle checkpoints 6 and cell cycle-regulatory molecules, including cyclins and cyclindependent kinases. [7][8][9] Aurora serine/threonine kinases localize in the centrosome and play a crucial role in cell division by regulating chromatid segregation in mitotic cells 10 ; moreover, defective chromatid segregation causes genetic instability, leading to tumorigenesis. 11 They were first identified in Xenopus Eg2, yeast Ipl1, and Drosophila aurora.…”

A vector-based short hairpin RNA targeting Aurora A inhibits breast cancer growth

“…In pacreatic cancer, colorectal cancer, non-small cell lung cancer and multiple myeloma cell lines, specific suppression of expression of Aurora A lead to G2-M arrest and apoptosis, and can enhance chemosensitivity and radiation response (18,37,38). It is reported that Aurora A activates Akt-induced cell survival and chemoresistance in a p53-dependent manner in ovarian cancer cells (39).…”