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

• Published in: Frontiers in cell and developmental biology 2022-08, Vol.10, p.935023-935023
• Main Authors: Manni, Sabrina, Pesavento, Maria, Spinello, Zaira, Saggin, Lara, Arjomand, Arash, Fregnani, Anna, Quotti Tubi, Laura, Scapinello, Greta, Gurrieri, Carmela, Semenzato, Gianpietro, Trentin, Livio, Piazza, Francesco
• Format: Article
• Language: English
• Subjects: Cell and Developmental Biology; CK2; ibrutinib; mantle cell lymphoma; target therapy; venetoclax
• ISSN: 2296-634X; 2296-634X
• DOI: 10.3389/fcell.2022.935023

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.