title: 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.
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.
authors.affiliation: Clinic for Internal Medicine 1, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106 Freiburg, Germany.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Illert
authors.affiliation: Department of Internal Medicine III, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Seitz
authors.affiliation: Clinic for Internal Medicine 1, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106 Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rummelt
authors.affiliation: Clinic for Internal Medicine 1, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106 Freiburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kreutmair
authors.affiliation: The Norwegian Structural Biology Centre, Departments of Chemistry and Pharmacy, University of Tromsø, Tromsø, Norway.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Engh
authors.affiliation: EMD-Serono Research and Development Institute, Inc., Billerica, Massachusetts, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Goodstal
authors.affiliation: Department of Internal Medicine III, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Clinic for Internal Medicine 1, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106 Freiburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Clinic for Internal Medicine 1, Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106 Freiburg, Germany.
authors.forename: Nikolas
authors.initials: N
authors.lastname: von Bubnoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009636:Norbornanes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C000592140:MSC1992371A; D009636:Norbornanes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl; C576921:AURKB protein, human; D064107:Aurora Kinase B; C523797:danusertib