title: Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias.
abstract: Drug resistance resulting from emergence of imatinib-resistant BCR-ABL point mutations is a significant problem in advanced-stage chronic myelogenous leukemia (CML). The BCR-ABL inhibitor, nilotinib (AMN107), is significantly more potent against BCR-ABL than imatinib, and is active against many imatinib-resistant BCR-ABL mutants. Phase 1/2 clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these 2 agents has clinical value. However, simultaneous, rather than sequential, administration of 2 BCR-ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here, we show that exposure of a variety of BCR-ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR-ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in antileukemic activity, compared with each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR-ABL kinase inhibitors is warranted.
authors.affiliation: Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Laurie
authors.initials: L
authors.lastname: Catley
authors.forename: Renee D
authors.initials: RD
authors.lastname: Wright
authors.forename: Daisy
authors.initials: D
authors.lastname: Moreno
authors.forename: Lolita
authors.initials: L
authors.lastname: Banerji
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Juergen
authors.initials: J
authors.lastname: Mestan
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Jingrui
authors.initials: J
authors.lastname: Jiang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hall-Meyers
authors.forename: Linda
authors.initials: L
authors.lastname: Callahan
authors.forename: Jamie L
authors.initials: JL
authors.lastname: DellaGatta
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002460:Cell Line; D004359:Drug Therapy, Combination; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D019000:Phosphotyrosine / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019000:Phosphotyrosine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib