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

Liangshun You; Hui Liu; Jian Huang; Wanzhuo Xie; Jueying Wei; Xiujin Ye; Wenbin Qian

doi:10.18632/oncotarget.13951

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

Oncotarget. 2017 Jan 31;8(5):7777-7790. doi: 10.18632/oncotarget.13951.

Authors

Liangshun You¹, Hui Liu¹, Jian Huang², Wanzhuo Xie¹, Jueying Wei¹, Xiujin Ye¹, Wenbin Qian¹

Affiliations

¹ Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, P.R. China.
² Department of Hematology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, P.R. China.

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.

Keywords: BCR/ABL; JNJ-26854165; T315I mutation; chronic myeloid leukemia.

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Biomarkers, Tumor / antagonists & inhibitors
Biomarkers, Tumor / genetics*
Biomarkers, Tumor / metabolism
Cell Death / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Synergism
Enzyme Inhibitors / pharmacology*
Fusion Proteins, bcr-abl / antagonists & inhibitors
Fusion Proteins, bcr-abl / genetics*
Fusion Proteins, bcr-abl / metabolism
Gene Expression Regulation, Neoplastic
Humans
Imatinib Mesylate / pharmacology
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Mice, SCID
Mutation*
Proteasome Endopeptidase Complex / metabolism*
Protein Kinase Inhibitors / pharmacology
Proteolysis
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Time Factors
Tryptamines / pharmacology*
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
BCR-ABL1 fusion protein, human
Biomarkers, Tumor
Enzyme Inhibitors
Protein Kinase Inhibitors
TP53 protein, human
Tryptamines
Tumor Suppressor Protein p53
JNJ 26854165
Imatinib Mesylate
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
Fusion Proteins, bcr-abl
Proteasome Endopeptidase Complex