Inhibition of Aurora kinase B is important for biologic activity of the dual inhibitors of BCR-ABL and Aurora kinases R763/AS703569 and PHA-739358 in BCR-ABL transformed cells

Anna L Illert; Anna K Seitz; Christoph Rummelt; Stefanie Kreutmair; Richard A Engh; Samantha Goodstal; Christian Peschel; Justus Duyster; Nikolas von Bubnoff

doi:10.1371/journal.pone.0112318

Inhibition of Aurora kinase B is important for biologic activity of the dual inhibitors of BCR-ABL and Aurora kinases R763/AS703569 and PHA-739358 in BCR-ABL transformed cells

PLoS One. 2014 Nov 26;9(11):e112318. doi: 10.1371/journal.pone.0112318. eCollection 2014.

Authors

Anna L Illert¹, Anna K Seitz², Christoph Rummelt¹, Stefanie Kreutmair¹, Richard A Engh³, Samantha Goodstal⁴, Christian Peschel², Justus Duyster¹, Nikolas von Bubnoff¹

Affiliations

¹ Clinic for Internal Medicine 1, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106 Freiburg, Germany.
² Department of Internal Medicine III, Technical University of Munich, 81675 Munich, Germany.
³ The Norwegian Structural Biology Centre, Departments of Chemistry and Pharmacy, University of Tromsø, Tromsø, Norway.
⁴ EMD-Serono Research and Development Institute, Inc., Billerica, Massachusetts, United States of America.

Abstract

ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/AS703569 in Ba/F3- cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Aurora Kinase B / antagonists & inhibitors*
Aurora Kinase B / chemistry
Aurora Kinase B / genetics
Aurora Kinase B / metabolism
B-Lymphocytes / drug effects
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Base Sequence
Benzamides / pharmacology*
Cell Cycle / drug effects
Cell Line, Transformed
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Fusion Proteins, bcr-abl / antagonists & inhibitors*
Fusion Proteins, bcr-abl / chemistry
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism
Gene Expression
Humans
Mice
Molecular Docking Simulation
Molecular Sequence Data
Norbornanes / pharmacology*
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / pharmacology*
Pyrimidines / pharmacology*

Substances

Antineoplastic Agents
Benzamides
MSC1992371A
Norbornanes
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
Fusion Proteins, bcr-abl
AURKB protein, human
Aurora Kinase B
danusertib

Grants and funding

This work was supported by a grant to JD and NVB from the Bundesministerium für Bildung und Forschung (NGFNplus), and from the Wilhelm-Sander Stiftung, by a grant to JD from the Deutsche Forschungsgemeinschaft (SFB 684/A11), and by a grant to NVB by the Gertrud-und-Erwin-Ruppert-Stiftung München. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.