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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3915-3921.
Prepublished online as a Blood First Edition Paper on January 9, 2007; DOI 10.1182/blood-2006-07-037671.
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Submitted July 25, 2006
Accepted December 24, 2006
Targeting aurora kinases as therapy in multiple myeloma
Yijiang Shi, Tony Reiman, Weiqun Li, Christopher A Maxwell, Subrata Sen, Linda Pilarski, Tracy R Daniels, Manuel L Penichet, Rick Feldman, and Alan Lichtenstein*
Division of Hematology, VA West LA-UCLA Medical School and Jonsson Cancer Center, Los Angeles, CA, United States
Dept of Oncology, University of Alberta and Cross Cancer Institute, Alberta, Canada
Origene Technologies, Rockville, MD, United States
Dept of Molecular Pathology, MD Anderson Cancer Center, Houston, TX, United States
Dept of Surgery, UCLA Medical School, Los Angeles, CA, United States
Dept of Cancer Research, Berlex Biosciences, Wayne, NJ, United States
* Corresponding author; email: alan.lichtenstein{at}med.va.gov.
The aurora kinases facilitate transit from G2 through cytokinesis and, thus, are targets in cancer therapy. Multiple myeloma (MM) is a malignancy characterized by genetic instability, suggesting a disruption of checkpoints that arrest cells at G2M when injury to the mitotic machinery occurs. Since deficient checkpoints would prevent cell cycle arrest and may render cells susceptible to apoptosis in mitosis and since aurora kinases are intermediaries in checkpoint pathways, we tested anti-myeloma effects of two agents that inhibit aurora kinases. Both inhibited growth of MM lines and primary myeloma samples at nM concentrations while having less of an effect on proliferating lymphocytes and hematopoietic cells. MM cells were not protected by IL-6 or activating mutations of Ras. Anti-myeloma effects included induction of tetraploidy followed by apoptosis. Apoptosis correlated with inhibition of aurora activity as shown by reduction of histone 3B phosphorylation. Ectopic expression of aurora A protected MM cells against aurora inhibitors but had no effect on apoptosis induced by velcade. As expression of RHAMM in MM contributes to genetic instability, we tested effects of RHAMM. RHAMM over-expression enhanced sensitivity to apoptosis and RHAMM silencing decreased sensitivity. These results suggest potential for aurora kinase inhibitors in MM especially in patients where RHAMM is over-expressed.
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