Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells.
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.
Evans
Robert
R
Department of Oncology, University of Alberta/Cross Cancer Institute, Edmonton, Alberta, Canada.
Naber
Claudia
C
Steffler
Tara
T
Checkland
Tamara
T
Keats
Jonathan
J
Maxwell
Christopher
C
Perry
Troy
T
Chau
Heidi
H
Belch
Andrew
A
Pilarski
Linda
L
Reiman
Tony
T
D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001853:Bone Marrow; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064096:Aurora Kinase A; D064127:Aurora Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576917:AURKA protein, human