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.
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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. / Gontarewicz, Artur; Balabanov, Stefan; von Amsberg, Gunhild; Panse, Jens; Schafhausen, Philippe; Bokemeyer, Carsten; Fiedler, Walter; Moll, Jürgen; Brümmendorf, Tim.
in: LEUKEMIA RES, Jahrgang 32, Nr. 12, 12, 2008, S. 1857-1865.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - 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.
AU - Gontarewicz, Artur
AU - Balabanov, Stefan
AU - von Amsberg, Gunhild
AU - Panse, Jens
AU - Schafhausen, Philippe
AU - Bokemeyer, Carsten
AU - Fiedler, Walter
AU - Moll, Jürgen
AU - Brümmendorf, Tim
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 32
SP - 1857
EP - 1865
JO - LEUKEMIA RES
JF - LEUKEMIA RES
SN - 0145-2126
IS - 12
M1 - 12
ER -