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

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

  • Oncotarget. 2017 Jun 13;8(24):38717-38730. doi: 10.18632/oncotarget.16314.
Masanobu Tsubaki 1,  Tomoya Takeda 1,  Toshiki Kino 1,  Kazuko Sakai 2,  Tatsuki Itoh 3,  Motohiro Imano 4,  Takashi Nakayama 5,  Kazuto Nishio 2,  Takao Satou 6,  Shozo Nishida 1
Affiliations

Affiliations

  • 1 Division of Pharmacotherapy, Kindai University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
  • 2 Department of Genome Biology, Kindai University School of Medicine, Osakasayama, Osaka, Japan.
  • 3 Department of Food Science and Nutrition, Kindai University School of Agriculture, Nara, Nara, Japan.
  • 4 Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka, Japan.
  • 5 Division of Chemotherapy, Kindai University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
  • 6 Department of Pathology, Kindai University School of Medicine, Osakasayama, Osaka, Japan.
PMID: 28418880 DOI: 10.18632/oncotarget.16314
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.

Keywords

ERK1/2; JNK; MET; chronic myeloid leukemia; imatinib resistance.

Figures
Products