title: All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to ponatinib.
abstract: The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients.
authors.affiliation: C3M/ INSERM U1065 Team Cell Death, Differentiation, Inflammation and Cancer, Nice, France.
authors.forename: Ophélie
authors.initials: O
authors.lastname: Cassuto
authors.forename: Maeva
authors.initials: M
authors.lastname: Dufies
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Guillaume
authors.initials: G
authors.lastname: Robert
authors.forename: Clémence
authors.initials: C
authors.lastname: Ginet
authors.forename: Alix
authors.initials: A
authors.lastname: Dubois
authors.forename: Amine
authors.initials: A
authors.lastname: Hamouda
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Fredéric
authors.initials: F
authors.lastname: Luciano
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Karsenti
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.forename: Jill Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Pascal
authors.initials: P
authors.lastname: Lenain
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007093:Imidazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D013844:Thiazoles; C545373:ponatinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib