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Tumor Discovery CK2 deregulation in non-small-cell lung cancer

1. Introduction 2. Materials and methods

Casein kinase-2 (CK2) is a constitutively active Ser/ 2.1. CSNK2 gene mutational burden in cancer
Thr-protein kinase frequently deregulated in cancer, cohorts
with broad tumor-supporting roles classified as “non- The cBioPortal for Cancer Genomics (https://www.
oncogene addiction”. The CK2 holoenzyme comprises cbioportal.org/) was used to retrieve data on the
1
two catalytic subunits (CSNK2A1 and CSNK2A2) and two mutational burden – specifically, the total frequency and
regulatory subunits (CSNK2B), which assemble as either types of alterations – of the CSNK2A1, CSNK2A2, and
homotetramers (CSNK2A1 /CSNK2B or CSNK2A2 / CSNK2B subunits. This data were sourced from the Pan-
2
2
2
CSNK2B ) or heterotetramers (CSNK2A1/CSNK2A2/ Cancer Analysis of Whole Genomes Consortium of the
2
2
CSNK2B ). In addition, CK2’s supramolecular structures,
2
spatiotemporal subunit associations, and functional International Cancer Genome Consortium and The Cancer
Samples with
Genome Atlas (TCGA) (Nature 2020).
14,15
specialization introduce further regulatory intricacies mutations and copy-number alterations (CNA) data were
in both health and disease. Notably, CK2 participates in selected across 38 tumor types, comprising 2683 samples
3
multiple tumor-related signaling cascades, promoting
aberrant cell proliferation, survival, and metastasis. from 2565 patients.
4
However, CK2’s unique biochemical features, vast range of For a more detailed analysis within NSCLC cohorts,
substrates, and multifaceted impact on signaling cascades cBioPortal was further queried for genetic alterations
have sparked debates about its viability as an oncology specific to CSNK2A1, CSNK2A2, and CSNK2B subunits
target. These discussions include inquiries about CK2’s in LUAD and LUSC. The select genomic profiles included
5,6
essentiality in cancer versus non-neoplastic tissues, as mutations, putative CNA from the Genome Identification
well as concerns regarding the specificity of current CK2 of Significant Targets in Cancer, and mRNA expression
inhibitors. 7,8 z-scores relative to normal samples (log RNA Seq V2
A myriad of natural and synthetic compounds with RSEM). For LUAD, the TCGA PanCancer Atlas cohort
diverse CK2 inhibition mechanisms has been described. (n = 566 samples) was interrogated, while for LUSC, the
9
Recent compounds exhibit ATP-competitive or dual TCGA PanCancer Atlas cohort (n = 487 samples) was used.
inhibition mechanisms, targeting the ATP-binding site and Driver feature prediction, based on the mutational
an allosteric pocket unique to CK2. However, only two frequency, distribution, and functional impact of
7,10
distinct CK2 inhibitors have reached clinical application: individual mutations, was performed through the IntOgene
the synthetic peptide CIGB-300 and the small molecule platform, which interrogates 66 cancer types across 221
CX-4945. 11,12 Despite extensive pre-clinical research, studies (n = 28,076 samples; https://www.intogen.org/
translational and clinical data on CK2 remain limited and search). Cancer driver annotations were obtained from
16
sparse, and its role as a validated oncology target is yet to OncoKB™MSK’s Precision Oncology Knowledge Base
be established. 13 (OncoKB) (https://www.oncokb.org/). 17
In this study, we interrogated multiomics cancer 2.2. CSNK2 gene expression in cancer
databases to investigate CK2 gene mutations and
deregulated expression in clinical samples. We performed Expression levels of CSNK2 genes across pan-cancer studies
meta-analyses to explore potential associations between were interrogated using data from the TCGA available
CK2 subunit expression and overall survival (OS) of non- through the University of Alabama at Birmingham
18
small-cell lung cancer (NSCLC) patients. Our analysis database (UALCAN) (https://ualcan.path.uab.edu).
centers on individual CK2 subunits, assuming subunit- Tumor and non-tumor samples are represented in red
specific functions across cancers, with a particular focus and blue, respectively. Box-and-whisker plots display gene
on two major NSCLC types: lung adenocarcinoma expression levels, including maximum, upper quartile,
(LUAD) and lung squamous cell carcinoma (LUSC). median, lower quartile, and minimum values. Statistical
CK2 protein subunit levels were measured by performing comparisons were conducted using the Student’s t-test with
immunohistochemistry (IHC) in LUAD and LUSC patient unequal variances. The following TCGA tumor subtypes
samples and correlated with selected clinicopathological were included: Bladder urothelial carcinoma, breast
features. Finally, by measuring two canonical CK2 invasive carcinoma, cervical squamous cell carcinoma,
substrates as indicators of in situ CK2 enzymatic activity, cholangiocarcinoma, colon adenocarcinoma, esophageal
we demonstrated that CK2 upregulation in LUAD and carcinoma, glioblastoma multiforme, head-and-neck
LUSC corresponds with increased CK2 enzymatic activity squamous cell carcinoma, kidney chromophobe, kidney
in these NSCLC subtypes. renal clear cell carcinoma, kidney renal papillary cell

Volume 3 Issue 4 (2024) 2 doi: 10.36922/td.4571