Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-JUN N-terminal kinase inhibition.

Abstract

BACKGROUND:

The Philadelphia chromosome (Ph), which leads to the creation and expression of the fusion gene product BCR-ABL, underlines the pathogenesis of chronic myelogenous leukemia (CML) and a fraction of adult and pediatric acute B-lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitors (TKIs) have shown a remarkable clinical activity in patients with CML, but their efficacy in treating Ph+ B-ALL is limited. Identifying additional therapeutic targets is important for the effective treatment of Ph+ B-ALL.

METHODS:

Activation of the JNK signaling pathway in human and mouse BCR-ABL+ B-ALL cells with or without dasatinib treatment was analyzed by Western blotting. JNK was inhibited either by RNA interference or chemical inhibitors, such as JNK-IN-8. The effect of JNK inhibition with or without BCR-ABL TKI dasatinib on BCR-ABL+ B-ALL cells was analyzed by the CellTiter-Glo® Luminescent Cell Viability Assay. The in vivo effects of JNK-IN-8 and dasatinib alone or in combination were tested using a BCR-ABL induced B-ALL mouse model.

RESULTS:

We found that the c-JUN N-terminal kinase (JNK) signaling pathway is abnormally activated in both human and mouse BCR-ABL+ B-ALL cells, but the BCR-ABL TKI does not inhibit JNK activation in these cells. Inhibition of JNK, either by RNAi-mediated downregulation or by JNK inhibitors, could significantly reduce viability of Ph+ B-ALL cells. JNK inhibition by RNAi-mediated downregulation or JNK inhibitors also showed a synergistic effect with the BCR-ABL TKI, dasatinib, in killing Ph+ B-ALL cells in vitro. Furthermore, a potent JNK inhibitor, JNK-IN-8, in combination with dasatinib markedly improved the survival of mice with BCR-ABL induced B-ALL, as compared to the treatment with dasatinib alone.

CONCLUSIONS:

Our findings indicate that simultaneously targeting both BCR-ABL and JNK kinase might serve as a promising therapeutic strategy for Ph+ B-ALL.

• Authors: Xinhua Xiao, Ping Liu, Donghe Li, Zhizhou Xia, Peihong Wang, Xiuli Zhang, Mingzhu Liu, Lujian Liao, Bo Jiao, Ruibao Ren
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 13 Issue 1 Pg. 80 (06 18 2020) ISSN: 1756-8722 [Electronic] England
• PMID: 32552902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (+)-JQ1 compound
• Anthracenes
• Azepines
• BCR-ABL1 fusion protein, human
• Benzamides
• JNK-IN-8
• MYC protein, human
• Neoplasm Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• Pyridines
• Pyrimidines
• RNA, Small Interfering
• Triazoles
• pyrazolanthrone
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• JNK Mitogen-Activated Protein Kinases
• Dasatinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Anthracenes (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Azepines (administration & dosage)
• Benzamides (administration & dosage)
• Cell Line, Tumor
• Dasatinib (administration & dosage)
• Drug Screening Assays, Antitumor
• Female
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Humans
• Imatinib Mesylate (administration & dosage)
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Male
• Mice
• Mice, Inbred BALB C
• Molecular Targeted Therapy
• Neoplasm Proteins (antagonists & inhibitors)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
• Protein Kinase Inhibitors (administration & dosage)
• Proto-Oncogene Proteins c-myc (biosynthesis)
• Pyridines (administration & dosage)
• Pyrimidines (administration & dosage)
• RNA Interference
• RNA, Small Interfering (genetics, pharmacology)
• Radiation Chimera
• Random Allocation
• Signal Transduction (drug effects)
• Triazoles (administration & dosage)