Affiliation:
1. Department of Medicine, Division of Hematology, University of Padova, Padova, Italy
Abstract
Background:
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, being a suitable pharmacological target in DLBCL, is unknown.
Objective:
The objective was 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 and to survey the
changes in signaling molecules downstream BCR upon CK2 inhibition.
Method:
A panel of GC and ABC DLBCL cells was 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.
Results:
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.
Conclusion:
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 the
DLBCL.
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Drug Discovery,Pharmacology,Oncology
Cited by
11 articles.
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