Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma.
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 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.
Hose
Dirk
D
Medizinische Klinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany. dirk.hose@med.uni-heidelberg.de
Rème
Thierry
T
Meissner
Tobias
T
Moreaux
Jérôme
J
Seckinger
Anja
A
Lewis
Joe
J
Benes
Vladimir
V
Benner
Axel
A
Hundemer
Michael
M
Hielscher
Thomas
T
Shaughnessy
John D
JD
Barlogie
Bart
B
Neben
Kai
K
Krämer
Alwin
A
Hillengass
Jens
J
Bertsch
Uta
U
Jauch
Anna
A
De Vos
John
J
Rossi
Jean-François
JF
Möhler
Thomas
T
Blake
Jonathon
J
Zimmermann
Jürgen
J
Klein
Bernard
B
Goldschmidt
Hartmut
H
D017209:Apoptosis / Q000187:drug effects*; D064108:Aurora Kinase C; D064127:Aurora Kinases; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007399:Interphase / Q000235:genetics; D009101:Multiple Myeloma / Q000201:enzymology / Q000473:pathology* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D014407:Tumor Cells, Cultured; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064108:Aurora Kinase C; D064127:Aurora Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576927:AURKC protein, human