PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on Imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and Aurora kinases.
Emergence of resistance to Imatinib complicates the treatment of chronic myeloid leukemia (CML). Second-generation Bcr-Abl inhibitors are capable to overcome resistance mediated by most mutations except T315I. As this mutation is causative for approximately 20% of clinically observed resistances, the need for novel treatment strategies becomes obvious. Here, we report on a novel kinase inhibitor PHA-680626 exhibiting strong inhibitory activity on both Bcr-Abl and Aurora kinases. Significant anti-proliferative and pro-apoptotic effects were observed in human BCR-ABL positive cell lines and murine BaF3 cells ectopically expressing wt BCR-ABL or the Imatinib-resistant BCR-ABL mutants M351T, E255K and, T315I. Treatment with PHA-680626 decreased phosphorylation of CrkL and histone H3. As CrkL represents a typical downstream target of Bcr-Abl while histone H3 phosphorylation is an indicator for Aurora kinase B activity, these findings indicate that effects of PHA-680626 are mediated via inhibition of both pathways. Moreover, high anti-proliferative activity of PHA-680626 was observed in primary CD34+ cells derived from CML patients at diagnosis or in blast crisis as well as from an individual harbouring the T315I mutation. Thus, both Bcr-Abl and Aurora kinase inhibition contribute to the efficacy of PHA-680626 against Imatinib-resistant BCR-ABL positive leukemias, particularly those harbouring the T315I mutation.
Onkologisches Zentrum, Universitäts-Klinikum Hamburg-Eppendorf, Hamburg, Germany.
Artur
A
Gontarewicz
Stefan
S
Balabanov
Gunhild
G
Keller
Jens
J
Panse
Philippe
P
Schafhausen
Carsten
C
Bokemeyer
Walter
W
Fiedler
Jürgen
J
Moll
Tim H
TH
Brümmendorf
D015703:Antigens, CD / Q000187:drug effects; D018952:Antigens, CD34 / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; C534137:PHA 680626; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases