Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells.

Abstract

Resistance to the breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitor (TKI) imatinib poses a major problem when treating chronic myeloid leukemia (CML). Imatinib resistance often results from a secondary mutation in BCR-ABL1. However, in the absence of a mutation in BCR-ABL1, the basis of BCR-ABL1-independent resistance must be elucidated. To gain insight into the mechanisms of BCR-ABL1-independent imatinib resistance, we performed an array-based comparative genomic hybridization. We identified various resistance-related genes, and focused on MET. Treatment with a MET inhibitor resensitized K562/IR cells to BCR-ABL1 TKIs. Combined treatment of K562/IR cells with imatinib and a MET inhibitor suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) activation, but did not affect AKT activation. Our findings implicate the MET/ERK and MET/JNK pathways in conferring resistance to imatinib, providing new insights into the mechanisms of BCR-ABL1 TKI resistance in CML.

• Authors: Masanobu Tsubaki, Tomoya Takeda, Toshiki Kino, Kazuko Sakai, Tatsuki Itoh, Motohiro Imano, Takashi Nakayama, Kazuto Nishio, Takao Satou, Shozo Nishida
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 24 Pg. 38717-38730 (Jun 13 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28418880 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Protein Kinase Inhibitors
• Imatinib Mesylate
• MET protein, human
• Proto-Oncogene Proteins c-met
• Fusion Proteins, bcr-abl

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Humans
• Imatinib Mesylate (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
• Male
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays