title: Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I.
abstract: The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34(+) cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.
authors.affiliation: Klinik für Onkologie und Hämatologie, Universitäres Cancer Center, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Gontarewicz
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.forename: Gunhild
authors.initials: G
authors.lastname: Keller
authors.forename: Riccardo
authors.initials: R
authors.lastname: Colombo
authors.forename: Alessio
authors.initials: A
authors.lastname: Graziano
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Daniel
authors.initials: D
authors.lastname: Benten
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Moll
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D001549:Benzamides; C082869:CRKL protein; D004273:DNA, Neoplasm; D050505:Mutant Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib