title: Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate.
abstract: Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.
authors.affiliation: Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Tipping
authors.forename: S
authors.initials: S
authors.lastname: Baluch
authors.forename: D J
authors.initials: DJ
authors.lastname: Barnes
authors.forename: D R
authors.initials: DR
authors.lastname: Veach
authors.forename: B M
authors.initials: BM
authors.lastname: Clarkson
authors.forename: W G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: F X
authors.initials: FX
authors.lastname: Mahon
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
mesh_terms: D000818:Animals; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000032:analysis* / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases