Abstract
Genetic instability and cellular proliferation have been associated with Aurora-kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of Aurora-A, -B and -C was determined by Affymetrix DNA-microarrays in 784 samples including two independent sets of 233 and 345 CD138-purified myeloma-cells from previously untreated myeloma-patients. Chromosomal aberrations were assessed by comprehensive iFISH and proliferation of primary myeloma-cells by propidium-iodine staining. The effect of the clinical Aurora-kinase inhibitor VX680 on proliferation of 20 human-myeloma-cell-lines and survival of 5 primary myeloma-cell-samples was tested. We found Aurora-A and -B to be expressed at varying frequencies in primary myeloma-cells of different patient-cohorts, Aurora-C in testis-samples only. Myeloma-cell samples with detectable vs. absent Aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations present (aneuploidy) nor of subclonal aberrations (chromosomal instability). VX680 induces apoptosis in all myeloma-cell-line- and primary myeloma-cell-samples tested. Presence of Aurora-A expression delineates significantly inferior event-free and overall-survival in two independent cohorts of patients undergoing high-dose chemotherapy, independent of conventional prognostic factors, i.e. serum-beta2-microglobulin or ISS-stage. In conclusion, using gene expression profiling, Aurora-kinase inhibitors as promising therapeutic option for newly-diagnosed patients can be tailoredly given to patients with adverse prognosis, expressing Aurora-A.