title: Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells.
abstract: Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.
authors.affiliation: Division of Hematology/Oncology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States.
authors.forename: Tri
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Division of Hematology/Oncology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States.
authors.forename: Elisa
authors.initials: E
authors.lastname: Hawkins
authors.affiliation: Division of Hematology/Oncology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States.
authors.forename: Akhil
authors.initials: A
authors.lastname: Kolluri
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States.
authors.forename: Maciej
authors.initials: M
authors.lastname: Kmieciak
authors.affiliation: Division of Hematology/Oncology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States.
authors.forename: Haeseong
authors.initials: H
authors.lastname: Park
authors.affiliation: Division of Hematology/Oncology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Division of Hematology/Oncology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States; Department of Biochemistry, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States; Department of Pharmacology, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States; Human and Molecular Genetics, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States; Massey Cancer Center, Virginia Commonwealth University Health Sciences Center, Richmond, VA, United States. Electronic address: stgrant@vcu.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D019943:Amino Acid Substitution; D000814:Aniline Compounds / Q000819:agonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001570:Benzodiazepinones / Q000819:agonists / Q000494:pharmacology; D000071877:Checkpoint Kinase 1; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles / Q000819:agonists / Q000494:pharmacology; D010879:Piperazines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000819:agonists / Q000494:pharmacology; D011743:Pyrimidines; D011804:Quinolines / Q000819:agonists / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D001570:Benzodiazepinones; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; C532366:PF 00477736; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D016044:Fusion Proteins, bcr-abl; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: BCR/ABL; Bosutinib; Chk1 inhibitor; Chronic myeloid leukemia