Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.

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 -