Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

Abstract

Protein kinase CK2 (designated CSNK2) is a constitutively active protein kinase with a vast repertoire of putative substrates that has been implicated in several human cancers, including cancer of the breast, lung, colon, and prostate, as well as hematologic malignancies. On the basis of these observations, CSNK2 has emerged as a candidate for targeted therapy, with two CSNK2 inhibitors in ongoing clinical trials. CX-4945 is a bioavailable small-molecule ATP-competitive inhibitor targeting its active site, and CIGB-300 is a cell-permeable cyclic peptide that prevents phosphorylation of the E7 protein of HPV16 by CSNK2. In preclinical models, either of these inhibitors exhibit antitumor efficacy. Furthermore, in combinations with chemotherapeutics such as cisplatin or gemcitabine, either CX-4945 or CIGB-300 promote synergistic induction of apoptosis. While CSNK2 is a regulatory participant in many processes related to cancer, its potential to modulate caspase action may be particularly pertinent to its emergence as a therapeutic target. Because the substrate recognition motifs for CSNK2 and caspases are remarkably similar, CSNK2 can block the cleavage of many caspase substrates through the phosphorylation of sites adjacent to cleavage sites. Phosphoproteomic strategies have also revealed previously underappreciated roles for CSNK2 in the phosphorylation of several key constituents of DNA damage and DNA repair pathways. Going forward, applications of proteomic strategies to interrogate responses to CSNK2 inhibitors are expected to reveal signatures for CSNK2 inhibition and molecular insights to guide new strategies to interfere with its potential to inhibit caspase action or enhance the susceptibility of cancer cells to DNA damage. Clin Cancer Res; 22(12); 2840-7. Ó2016 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: P.S. Steeg reports receiving commercial research grants from Genentech. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflicts of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the role of protein kinase CK2 (CSNK2) in cellular processes that underlie malignancy, including its capacity to interfere with caspase action and involvement in DNA repair pathways, and the biological rationale of CSNK2 inhibitors as promising candidates for novel therapeutic strategies.

Protein Kinase CK2 Controls the Fate between Th17 Cell and Regulatory T Cell Differentiation

“…CK2 is involved in a vast number of biological processes, with more that 2,000 putative phosphorylation sites in the human proteome (6). Our findings document an important role for CK2 in adaptive immunity as a critical regulator of the Th17/Treg cell axis.…”

“…As such, CK2α/α′ can maintain catalytic activity in the absence of their association with CK2β, adding to the complexity of CK2 biology (3). Aberrant CK2 activity is present in a number of tumors, promoting anti-apoptotic and pro-angiogenic mechanisms that favor tumor survival and growth, and is therefore a promising target for cancer therapy (4–6). CX-4945, an ATP-competitive small molecule inhibitor of both catalytic subunits of CK2, is one of the most specific inhibitors of CK2 available and is currently in Phase 1 and 2 clinical trials for both solid and liquid tumors (6–8).…”

A Selective Biligand Inhibitor of CK2 Increases Caspase‐3 Activity in Cancer Cells and Inhibits Platelet Aggregation

“…Moreover,t he catalytic subunits of CK2 are enzymatically active in the presence or absence of the regulatory CK2 subunit, CK2b.T herefore, the substrate specificity of CK2 is regulated by means of its localization, phosphorylation, andp rotein-protein interactions. [5] The pleiotropic nature,role in many cellular processes, and constitutive activity of CK2 exemplify its importance in an umber of diseases including thrombosis, [6] multiple sclerosis, [7] but most expressively,cancer. [4] The abundance of substrate proteins of CK2 can relate the kinase to almost every signaling pathway in ac ell.…”

“…[4] The abundance of substrate proteins of CK2 can relate the kinase to almost every signaling pathway in ac ell. [5] Second, cancerc ells express high levels of CK2, and inhibition of CK2 leads to cancer cell death. [5] The pleiotropic nature,role in many cellular processes, and constitutive activity of CK2 exemplify its importance in an umber of diseases including thrombosis, [6] multiple sclerosis, [7] but most expressively,cancer.…”

“…For example, substrates of CK2 are regulators of protein folding (Hsp90 and Cdc37, Figure 1A), cell growth and proliferation (MAP2K2 and MEN1), DNA damage response (MDC1a nd RAD51), and apoptosis (CASP3 and PTEN, Figure 1B). [5] The pleiotropic nature,role in many cellular processes, and constitutive activity of CK2 exemplify its importance in an umber of diseases including thrombosis, [6] multiple sclerosis, [7] but most expressively,cancer. [8] Twoa spects reflect the significance of the role of CK2 in cancer.F irst, CK2 regulates nearly all cellular processes that are essential for cancer development.…”