title: The novel anticancer agent JNJ-26854165 is active in chronic myeloid leukemic cells with unmutated BCR/ABL and T315I mutant BCR/ABL through promoting proteosomal degradation of BCR/ABL proteins.
abstract: Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant. The response to JNJ-26854165 is associated with the downregulation of BCR/ABL dependently of proteosome activation. Moreover, in all tested CML cells, with the exception of T315I mutation cells, combining JNJ-26854165 and tyrosine kinase inhibitor (TKI) Imatinib or PD180970 leads to a synergistic effect. In conclusion, our results suggest that JNJ-26854165, used either alone or in combination with TKIs, represents a promising novel targeted approach to overcome TKI resistance and improve patient outcome in CML.
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Liangshun
authors.initials: L
authors.lastname: You
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Hematology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Wanzhuo
authors.initials: W
authors.lastname: Xie
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Jueying
authors.initials: J
authors.lastname: Wei
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Xiujin
authors.initials: X
authors.lastname: Ye
authors.affiliation: Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Qian
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016513:Mice, SCID; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014363:Tryptamines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D014363:Tryptamines; D016159:Tumor Suppressor Protein p53; C568210:JNJ 26854165; D000068877:Imatinib Mesylate; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016044:Fusion Proteins, bcr-abl; D046988:Proteasome Endopeptidase Complex
keywords: BCR/ABL; JNJ-26854165; T315I mutation; chronic myeloid leukemia