Reference Detail

Ref Type Journal Article
PMID (28460620)
Authors Mandato E, Nunes SC, Zaffino F, Casellato A, Macaccaro P, Tubi LQ, Visentin A, Trentin L, Semenzato G, Piazza F
Title CX-4945, a selective inhibitor of casein kinase 2, synergizes with B cell receptor signaling inhibitors in inducing diffuse large B cell lymphoma cell death.
Journal Current cancer drug targets
Vol
Issue
Date 2017 Apr 26
URL
Abstract Text Approximately one third of Diffuse Large B cell Lymphomas (DLBCL) are refractory or relapse. Novel therapeutic approaches under scrutiny include inhibitors of B-cell receptor (BCR) signaling. Protein kinase CK2 propels survival, proliferation and stress response in solid and hematologic malignancies and promotes a "non-oncogene addiction" phenotype. Whether this kinase regulates BCR signaling thus being a suitable pharmacological target in DLBCL is unknown.To establish if CK2 controls DLBCL cell survival and the BCR signaling; to check if the combination of CK2 inhibitor CX-4945 and BCR blockers Ibrutinib and Fostamatinib is more effectively cytotoxic for DLBCL cells than the single agents; to survey the changes in signaling molecules downstream BCR upon CK2 inhibition.A panel of GC and ABC DLBCL cells were treated with CX-4945 and Fostamatinib or Ibrutinib. BCR signaling was assayed by intracellular Ca++ measurement and looking at the phosphorylation of signaling molecules. The effects on cell survival were assessed by flow cytometry, western blot and MTT assays.CK2 inhibition with CX-4945 causes DLBCL cell death. CX-4945 impaired AKT phosphorylation and intracellular Ca++ mobilization upon BCR engagement. The CK2 inhibitor acted synergistically with either the SYK inhibitor Fostamatinib or the BTK inhibitor Ibrutinib in inducing DLBCL cell death. CX-4945 was equally effective in GC and ABC DLBCL subtypes as well as in "double hit" DLBCL cell lines.These findings suggest a role for CK2 downstream of the BCR in controlling survival pathways crucial for cell growth of different DLBCL subtypes. Also, the use of CX-4945 in combination with BCR signaling blockers could represent a novel rational therapeutic approach in DLBCL.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown diffuse large B-cell lymphoma not applicable Fostamatinib + Silmitasertib Preclinical - Cell culture Actionable In a preclinical study, the combination of Silmitasertib (CX-4945) and Fostamatinib (R788) worked synergistically to decrease cell viability and resulted in increased apoptosis and decreased AKT phosphorylation in ABC and GCB-type diffuse large B-cell lymphoma cell lines in culture (PMID: 28460620). 28460620
Unknown unknown diffuse large B-cell lymphoma not applicable Ibrutinib + Silmitasertib Preclinical - Cell culture Actionable In a preclinical study, the combination of Silmitasertib (CX-4945) and Imbruvica (ibrutinib) worked synergistically to decrease cell viability and resulted in increased apoptosis and decreased AKT phosphorylation in ABC and GCB-type diffuse large B-cell lymphoma cell lines in culture (PMID: 28460620). 28460620