US EPA

5739681 

Journal Article 

Inhibition of protein kinase CK2 by CX-5011 counteracts imatinib-resistance preventing rpS6 phosphorylation in chronic myeloid leukaemia cells: new combined therapeutic strategies 

Salizzato, V; Borgo, C; Cesaro, L; Pinna, LA; Donella-Deana, A 

2016 

1 

Oncotarget
ISSN: 1949-2553 

Oncotarget. 

7 

14 

18204-18. [Oncotarget] 

English 

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder promoted by the constitutive tyrosine kinase activity of Bcr-Abl oncoprotein. Although treatment with the Bcr-Abl-inhibitor imatinib represents the first-line therapy against CML, almost 20-30% of patients develop chemotherapeutic resistance and require alternative therapy. Here we show that a strong hyper-phosphorylation/activation of ERK1/2, Akt Ser473, and 40S ribosomal protein S6 (rpS6) is detectable in imatinib-resistant KCL22 and K562 CML cells as compared to the -sensitive cell variants. In imatinib-resistant CML cells, high concentration of imatinib is required to strongly inhibit Bcr-Abl, ERK1/2 and Akt Ser473 phosphorylation, but under these conditions the phosphorylation of rpS6, a common downstream effector of MEK/ERK1/2 and PI3K/Akt/mTOR pathways is only slightly reduced. By contrast, down-regulation of the protein kinase CK2 by the inhibitor CX-5011 or by silencing the CK2 subunits does not affect the activation state of MEK/ERK1/2 or PI3K/Akt/mTOR signalling, but causes a drop in rpS6 phosphorylation in parallel with reduced protein synthesis. CK2-inhibition by CX-5011 induces cell death by apoptosis and acts synergistically with imatinib or the MEK-inhibitor U0126 in reducing the viability of imatinib-resistant CML cells. The ternary mixture containing CX-5011, imatinib and U0126 represents the most effective synergistic combination to counteract CML cell viability. These results disclose a novel CK2-mediated mechanism of acquired imatinib-resistance resulting in hyper-phosphorylation of rpS6. We suggest that co-targeting CK2 and MEK protein kinases is a promising strategy to restore responsiveness of resistant CML cells to imatinib. 

Antineoplastic Agents/pharmacology; Antineoplastic Combined Chemotherapy Protocols/pharmacology; Apoptosis/drug effects; Butadienes/pharmacology; Casein Kinase II/antagonists & inhibitors/genetics; Cell Survival/drug effects; Drug Resistance, Neoplasm/drug effects; Drug Synergism; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases/metabolism; Fusion Proteins, bcr-abl/antagonists & inhibitors; Imatinib Mesylate/pharmacology; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy; MAP Kinase Signaling System/drug effects; Nitriles/pharmacology; Phosphorylation/drug effects; Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins c-akt/metabolism; Pyrimidines/pharmacology; Quinolines/pharmacology; RNA Interference; RNA, Small Interfering/genetics; Ribosomal Protein S6/metabolism; Tumor Cells, Cultured