Protein Kinase CK2 represents a new target to boost Ibrutinib and Venetoclax induced cytotoxicity in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an incurable B cell non-Hodgkin lymphoma, characterized by frequent relapses. In the last decade, the pro-survival pathways related to BCR signaling and Bcl-2 have been considered rational therapeutic targets in B cell derived lymphomas. The BTK inhibitor Ibrutinib and the Bcl-2 inhibitor Venetoclax are emerging as effective drugs for MCL. However, primary and acquired resistance also to these agents may occur. Protein Kinase CK2 is a S/T kinase overexpressed in many solid and blood-derived tumours. CK2 promotes cancer cell growth and clonal expansion, sustaining pivotal survival signaling cascades, such as the ones dependent on AKT, NF-κB, STAT3 and others, counteracting apoptosis through a “non-oncogene” addiction mechanism. We previously showed that CK2 is overexpressed in MCL and regulates the levels of activating phosphorylation on S529 of the NF-κB family member p65/RelA. In the present study, we investigated the effects of CK2 inactivation on MCL cell proliferation, survival and apoptosis and this kinase’s involvement in the BCR and Bcl-2 related signaling. By employing CK2 loss of function MCL cell models, we demonstrated that CK2 sustains BCR signaling (such as BTK, NF-κB and AKT) and the Bcl-2-related Mcl-1 expression. CK2 inactivation enhanced Ibrutinib and Venetoclax-induced cytotoxicity. The demonstration of a CK2-dependent upregulation of pathways that may antagonize the effect of these drugs may offer a novel strategy to overcome primary and secondary resistance.

CK2β-regulated signaling controls B cell differentiation and function

“…These latter are required for substrate recruitment and kinase activity modulation (10). CK2 has been found overexpressed in a wide array of solid and hematologic tumors (11-15) and shown to sustain survival and proliferation of malignant B cells in chronic lymphocytic leukemia, multiple myeloma, mantle cell lymphoma, B-acute lymphoblastic leukemia and diffuse large B cell lymphoma (DLBCL) (13,(16)(17)(18)(19)(20)(21)(22). Multiple proteins taking part in hemo-lymphopoiesis are CK2 substrates, however, the physiological role of this kinase in B cell biology has been poorly explored.…”

Protein kinase CK2α is overexpressed in classical hodgkin lymphoma, regulates key signaling pathways, PD-L1 and may represent a new target for therapy

“…In this study, we have provided strong evidence that, in accordance with the paradigm known as “non-oncogene dependence” ( 18 , 42 ), overexpression of CK2α is believed to be responsible for pivotal mechanisms of cell proliferation and survival also in cHL.…”

“…Previously, we and other groups demonstrated that both CK2α and CK2β were overexpressed and essential for neoplastic cell growth. Inhibition of CK2 triggered apoptosis in neoplastic cells of multiple myeloma ( 30 ), acute leukemias ( 26 ), and non-Hodgkin lymphomas ( 18 , 25 ), without a significant impact on normal lymphocytes ( 31 ). However, the role of CK2 in cHL is unknown and has not been investigated yet.…”

“…( 41 ) in chronic lymphocytic leukemia, or Manni et al. ( 18 ) in mantle cell lymphoma, suggest that combination therapies with CX- potentially increase treatment response, particularly for drug-refractory patients. Furthermore, the inhibition of CK2 might contribute to achieve a synergistic treatment effect, even when used in combination with checkpoint inhibitors.…”

“…It is well documented that CK2 is involved in a wide range of biological processes, such as cell proliferation, differentiation, apoptosis and DNA damage repair ( 14 , 15 ). Our group has demonstrated that both CK2α and CK2β subunits are overexpressed in acute leukemias, multiple myeloma and non-Hodgkin lymphomas ( 15 – 18 ). CK2 mediates the phosphorylation of NF-κB p65 (RelA) directly on Serine 529 (S529), of STAT3 on S727 and of AKT on S129, promoting the survival of neoplastic cells as well as drug resistance ( 19 ).…”