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

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

The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation impacts multiple cellular processes such as growth, proliferation, and survival. Several abnormalities in this pathway have been documented over the years, and these alterations were shown to have great implications in tumorigenesis and resistance to chemotherapy. Thus, multiple Akt inhibitors have been developed and tested in adult tumors, and some of them are currently undergoing phase I, II, and III clinical trials for distinct cancers that arise during adulthood. Despite that, the impact of these inhibitors is still not fully understood in pediatric tumors, and Akt-specific targeting seems to be a promising approach to treat children affected by cancers. This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors. 

Targeting Akt/PKB in Pediatric Tumors: A Review From Preclinical to Clinical Trials.

The association of protein kinase CK2 (formerly casein kinase II or 2) with cell growth and proliferation in cells was apparent at early stages of its investigation. A cancer-specific role for CK2 remained unclear until it was determined that CK2 was also a potent suppressor of cell death (apoptosis); the latter characteristic differentiated its function in normal versus malignant cells because dysregulation of both cell growth and cell death is a universal feature of cancer cells. Over time, it became evident that CK2 exerts its influence on a diverse range of cell functions in normal as well as in transformed cells. As such, CK2 and its substrates are localized in various compartments of the cell. The dysregulation of CK2 is documented in a wide range of malignancies; notably, by increased CK2 protein and activity levels with relatively moderate change in its RNA abundance. High levels of CK2 are associated with poor prognosis in multiple cancer types, and CK2 is a target for active research and testing for cancer therapy. Aspects of CK2 cellular roles and targeting in cancer are discussed in the present review, with focus on nuclear and mitochondrial functions and prostate, breast and head and neck malignancies. 

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Protein kinase CK2 – diverse roles in cancer cell biology and therapeutic promise

Despite recent advances in surgical and multimodal therapies, the overall survival (OS) of advanced colorectal cancer (CRC) patients remains low. Thus, discerning sensitive prognostic biomarkers to give the optimistic treatment for CRC patients is extremely critical. N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) play an important role in CRC progression. Nonetheless, few studies have focused on the impact of m6A-related lncRNAs on the prognosis, tumor microenvironment (TME) and treatment of CRC. In this study, 1707 m6A-related lncRNAs were identified through Pearson correlation analysis and Weighted co-expression network analysis (WGCNA) using The Cancer Genome Atlas (TCGA) cohort. Then, 28 m6A-related prognostic lncRNAs were screened by univariate Cox regression analysis, followed by identifying two clusters by consensus clustering analysis. A prognostic model consisted of 8 lncRNA signatures was constructed by the least absolute shrinkage and selection operator (LASSO). Kaplan–Meier curve analysis and a nomogram were performed to investigate the prognostic ability of this model. The risk score of prognostic model act as an independent risk factor for OS rate. Functional enrichment analysis indicated that lncRNA signatures related tumor immunity. The low-risk group characterized by increased microsatellite instability-high (MSI-H), mutation burden, and immunity activation, indicated favorable odds of OS. Moreover, the lncRNA signatures were significantly associated with the cancer stem cell (CSC) index and drug sensitivity. In addition, 3 common immune genes shared by the lncRNA signatures were screened out. We found that these immune genes were widely distributed in 2 cell types of TME. Finally, a ceRNA network was constructed to identify ZEB1-AS1 regulatory axis in CRC. We found that ZEB1-AS1 was significantly overexpressed in tumor tissues, and was related to the metastasis of EMT and the chemoresistance of 5-Fu in CRC. Therefore, our study demonstrated the important role of m6A-related lncRNAs in TME remodeling. Moreover, these results illustrated the levels of ZEB1-AS1 might be valuable for predicting the progression and prognosis of CRC, and further provided a new target for the diagnosis and treatment of CRC patients.

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Identification of N6-methylandenosine related lncRNA signatures for predicting the prognosis and therapy response in colorectal cancer patients

Protein kinase CK2 (CK2) is a ubiquitous holoenzyme involved in a wide array of developmental processes. The involvement of CK2 in events such as neurogenesis, cardiogenesis, skeletogenesis, and spermatogenesis is essential for the viability of almost all organisms, and its role has been conserved throughout evolution. Further into adulthood, CK2 continues to function as a key regulator of pathways affecting crucial processes such as osteogenesis, adipogenesis, chondrogenesis, neuron differentiation, and the immune response. Due to its vast role in a multitude of pathways, aberrant functioning of this kinase leads to embryonic lethality and numerous diseases and disorders, including cancer and neurological disorders. As a result, CK2 is a popular target for interventions aiming to treat the aforementioned diseases. Specifically, two CK2 inhibitors, namely CX-4945 and CIBG-300, are in the early stages of clinical testing and exhibit promise for treating cancer and other disorders. Further, other researchers around the world are focusing on CK2 to treat bone disorders. This review summarizes the current understanding of CK2 in development, the structure of CK2, the targets and signaling pathways of CK2, the implication of CK2 in disease progression, and the recent therapeutics developed to inhibit the dysregulation of CK2 function in various diseases.

https://www.mdpi.com/2221-3759/10/3/31/pdf?version=1659688409

The Role of Protein Kinase CK2 in Development and Disease Progression: A Critical Review

Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway This identifies mTOR as an attractive therapeutic target in HR B-ALL Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945) Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies

/pdf/dual-targeting-of-mtor-as-a-novel-therapeutic-approach-for-3b7bq212fn.pdf

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway.

Daniel Bogush

Papers

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2