Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.
Standard
Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro. / Balabanov, Stefan; Gontarewicz, Artur; von Amsberg, Gunhild; Raddrizzani, Laura; Balabanov, Melanie; Bosotti, Roberta; Moll, Jürgen; Jost, Edgar; Barett, Christine; Rohe, Imke; Bokemeyer, Carsten; Holyoake, Tessa L; Brümmendorf, Tim.
in: PLOS ONE, Jahrgang 6, Nr. 4, 4, 2011, S. 19164.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.
AU - Balabanov, Stefan
AU - Gontarewicz, Artur
AU - von Amsberg, Gunhild
AU - Raddrizzani, Laura
AU - Balabanov, Melanie
AU - Bosotti, Roberta
AU - Moll, Jürgen
AU - Jost, Edgar
AU - Barett, Christine
AU - Rohe, Imke
AU - Bokemeyer, Carsten
AU - Holyoake, Tessa L
AU - Brümmendorf, Tim
PY - 2011
Y1 - 2011
N2 - The success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance in vitro. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance in vitro, raising hope that this drug combination may also achieve more durable disease control in vivo.
AB - The success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance in vitro. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance in vitro, raising hope that this drug combination may also achieve more durable disease control in vivo.
KW - Humans
KW - Cell Line, Tumor
KW - Oligonucleotide Array Sequence Analysis
KW - Drug Synergism
KW - Apoptosis/drug effects
KW - Cell Differentiation/drug effects
KW - Cell Proliferation/drug effects
KW - Mutation/genetics
KW - Signal Transduction/drug effects
KW - Protein Kinase Inhibitors/pharmacology
KW - ATP-Binding Cassette Transporters/antagonists & inhibitors/genetics/metabolism
KW - Benzamides/pharmacology
KW - Clone Cells
KW - Drug Resistance, Neoplasm/drug effects/genetics
KW - Fusion Proteins, bcr-abl/antagonists & inhibitors/metabolism
KW - Gene Expression Regulation, Leukemic/drug effects
KW - Hematopoietic Stem Cells/drug effects/pathology
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology/genetics/pathology
KW - Neoplasm Proteins/antagonists & inhibitors/genetics/metabolism
KW - Piperazines/pharmacology
KW - Polyploidy
KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
KW - Pyrazoles/pharmacology
KW - Pyrimidines/pharmacology
KW - Humans
KW - Cell Line, Tumor
KW - Oligonucleotide Array Sequence Analysis
KW - Drug Synergism
KW - Apoptosis/drug effects
KW - Cell Differentiation/drug effects
KW - Cell Proliferation/drug effects
KW - Mutation/genetics
KW - Signal Transduction/drug effects
KW - Protein Kinase Inhibitors/pharmacology
KW - ATP-Binding Cassette Transporters/antagonists & inhibitors/genetics/metabolism
KW - Benzamides/pharmacology
KW - Clone Cells
KW - Drug Resistance, Neoplasm/drug effects/genetics
KW - Fusion Proteins, bcr-abl/antagonists & inhibitors/metabolism
KW - Gene Expression Regulation, Leukemic/drug effects
KW - Hematopoietic Stem Cells/drug effects/pathology
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology/genetics/pathology
KW - Neoplasm Proteins/antagonists & inhibitors/genetics/metabolism
KW - Piperazines/pharmacology
KW - Polyploidy
KW - Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
KW - Pyrazoles/pharmacology
KW - Pyrimidines/pharmacology
U2 - 10.1371/journal.pone.0019164
DO - 10.1371/journal.pone.0019164
M3 - SCORING: Journal article
VL - 6
SP - 19164
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
M1 - 4
ER -