title: The MEK1/2 inhibitor U0126 reverses imatinib resistance through down-regulating activation of Lyn/ERK signaling pathway in imatinib-resistant K562R leukemia cells.
abstract: Chronic myelogenous leukemia (CML) is triggered by the constitutively activated BCR-ABL oncoprotein and multiple downstream signaling pathways, including the Raf/MEK/ERK, Akt/mTOR, SRC, and STAT5 pathways. The BCR-ABL tyrosine kinase inhibitor imatinib is the standard treatment for CML. However, the development of imatinib resistance has become a new challenge for CML treatment. Here, we investigated the expression levels of the signaling pathways to explore the cause of imatinib resistance and seek new reversing drugs. Our results showed that abnormal activation of the BCR-ABL-independent Lyn/ERK signaling pathway was involved in imatinib-resistance of K562R cells. Furthermore, p-Lyn and p-ERK were up-regulated after treatment with imatinib alone. However, U0126, a MEK1/2 inhibitor, could counteract the up-regulation induced by imatinib, and the combination of imatinib and U0126 could overcome the resistance to imatinib in K562R cells. In conclusion, our studies suggest that the combination of imatinib and an inhibitor of the ERK signaling pathway may be effective in imatinib-resistant CML patients.
authors.forename: R
authors.initials: R
authors.lastname: Shi
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.forename: Y P
authors.initials: YP
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D007202:Indicators and Reagents; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D019061:src-Family Kinases / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002070:Butadienes; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; C113580:U 0126; D000068877:Imatinib Mesylate; C546842:MTOR protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C022616:thiazolyl blue