Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2

Abstract

Disturbance of protein kinase activity may result in dramatic consequences that often lead to cancer development and progression. In tumors of blood origin, both tyrosine kinases and serine/threonine kinases are altered by different types of mutations, critically regulating cancer hallmarks. CK1α and CK2 are highly conserved, ubiquitously expressed and constitutively active pleiotropic kinases, which participate in multiple biological processes. The involvement of these kinases in solid and blood cancers is well documented. CK1α and CK2 are overactive in multiple myeloma, leukemias and lymphomas. Intriguingly, they are not required to the same degree for the viability of normal cells, corroborating the idea of “druggable” kinases. Different to other kinases, mutations on the gene encoding CK1α and CK2 are rare or not reported. Actually, these two kinases are outside the paradigm of oncogene addiction, since cancer cells’ dependency on these proteins resembles the phenomenon of “non-oncogene” addiction. In this review, we will summarize the general features of CK1α and CK2 and the most relevant oncogenic and stress-related signaling nodes, regulated by kinase phosphorylation, that may lead to tumor progression. Finally, we will report the current data, which support the positioning of these two kinases in the therapeutic scene of hematological cancers.

CK1 Is a Druggable Regulator of Microtubule Dynamics and Microtubule-Associated Processes

“…Although the mutation rate of CSNK1D is very low, a TCGA database analysis from certain tumor tissues and tumor cell lines clearly indicates genomic amplification of CSNK1D with the highest frequency in lung cancer and bladder/urinary tract cancer ( Figure 2 ). Genomic alterations could explain that alterations in the expression levels in different cancer entities including urinary tract/bladder cancer [ 33 ], lung cancer [ 34 ], colorectal cancer [ 35 ], breast carcinomas [ 36 ], ductal pancreatic carcinomas [ 37 ], and blood cancer [ 38 , 39 ] (reviewed in [ 40 , 41 ]) contribute to tumorigenesis and tumor progression.…”

Meis1 supports leukemogenesis through stimulation of ribosomal biogenesis and Myc

“…With respect to application in patients, the current general CK2 inhibitors are suboptimal. It has been estimated that CK2 phosphorylates up to 20% of all proteins in a cell 22 . Therefore, CK2 inhibitors may have a small therapeutic window.…”

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

“…CK2 is a S/T kinase, composed by a tetramer of two catalytic CK2α (most represented) or CK2α’ and two regulatory CK2β subunits. CK2 promotes cancer cell proliferation and tumor progression by antagonizing extrinsic and intrinsic apoptosis in a “non-oncogene” addiction fashion ( Mandato et al, 2016 ; Spinello et al, 2021 ). CK2 also regulates cellular processes central for cancer biology (p53, Wnt/β-catenin, AKT and NF-kB survival signaling pathways) ( Spinello et al, 2021 ).…”