Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells
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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
Shozo Nishida, email: firstname.lastname@example.org
Keywords: chronic myeloid leukemia, imatinib resistance, MET, ERK1/2, JNK
Received: March 25, 2016 Accepted: February 20, 2017 Published: March 17, 2017
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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