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.
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. ©2016 AACR.
Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Adam J
AJ
Rabalski
Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Laszlo
L
Gyenis
Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. Department of Oncology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada. litchfi@uwo.ca.
David W
DW
Litchfield
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010619:Phenazines; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009287:Naphthyridines; D050725:Papillomavirus E7 Proteins; D010456:Peptides, Cyclic; D010619:Phenazines; D047428:Protein Kinase Inhibitors; C059731:oncogene protein E7, Human papillomavirus type 16; D000255:Adenosine Triphosphate; C555142:silmitasertib; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; C532510:CIGB-300