Oncotarget

Research Papers:

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

Masanobu Tsubaki, Tomoya Takeda, Toshiki Kino, Kazuko Sakai, Tatsuki Itoh, Motohiro Imano, Takashi Nakayama, Kazuto Nishio, Takao Satou and Shozo Nishida _

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Oncotarget. 2017; 8:38717-38730. https://doi.org/10.18632/oncotarget.16314

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Abstract

Masanobu Tsubaki1, Tomoya Takeda1, Toshiki Kino1, Kazuko Sakai2, Tatsuki Itoh3, Motohiro Imano4, Takashi Nakayama5, Kazuto Nishio2, Takao Satou6 and Shozo Nishida1

1Division of Pharmacotherapy, Kindai University School of Pharmacy, Kowakae, Higashi-Osaka, Japan

2Department of Genome Biology, Kindai University School of Medicine, Osakasayama, Osaka, Japan

3Department of Food Science and Nutrition, Kindai University School of Agriculture, Nara, Nara, Japan

4Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka, Japan

5Division of Chemotherapy, Kindai University School of Pharmacy, Kowakae, Higashi-Osaka, Japan

6Department of Pathology, Kindai University School of Medicine, Osakasayama, Osaka, Japan

Correspondence to:

Shozo Nishida, email: nishida@phar.kindai.ac.jp

Keywords: chronic myeloid leukemia, imatinib resistance, MET, ERK1/2, JNK

Received: March 25, 2016     Accepted: February 20, 2017     Published: March 17, 2017

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.


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