Casein Kinase 2 Inhibitor, CX-4945, as a Potential Targeted Anticancer Agent in Gastric Cancer

Abstract

Background/Aim: Casein kinase 2 (CK2) is involved in multiple cellular processes. Furthermore, its overexpression in several human cancers has been associated with tumor progression. In this study, we evaluated the efficacy of the CK2 inhibitor, CX-4945, in gastric cancer cell lines and explored the potential predictive biomarkers for CX-4945 sensitivity. Materials and Methods: The sensitivity to CX-4945 was screened in 49 gastric cancer cell lines by the MTT assay. The mRNA and protein expression of CK2 subunits (α and α') were determined using qRT-PCR and western blot. Furthermore, the activity of CK2α was measured by ELISA. Gene expression and mutations were analyzed via whole-exome and RNA sequencing. Results: The sensitivity to CX-4945 was determined by the inhibition rate (%) at the effective dose (10 μM) which ranged from-1% to 89% in 49 gastric cancer cell lines. CK2α', but not CK2α, mRNA expression was correlated with CX-4945 sensitivity. Conclusion: In this study, CX-4945 showed modest antitumor efficacy in gastric cancer cell lines. CK2 might represent a potential therapeutic target for gastric cancer. Gastric cancer is the most commonly diagnosed cancer in Korea and increased annual screenings indicated that the proportion of early gastric cancer increased to 73.6% of all cancer cases (1). Based on a Korea National Cancer Incidence Database (KNCI DB), gastric cancer is the second (15.2%) and third (9.5%) highest in males and females, respectively. Also, gastric cancer recorded as the forth (9.2%) and sixth (7.9%) highest cause of death in males and females, respectively (2). In America and Europe gastric cancer burden remains high (3). Several agents have been developed to treat metastatic gastric cancer including those targeting the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF) and hepatocyte growth factor receptor (HGFR/C-Met). However, except for trastuzumab and ramucirumab, most of them have failed to show efficacy in gastric cancer (4-6). A comprehensive understanding of gastric cancer biology is needed for new drug development (7, 8). Casein kinase 2 (CK2) is a serine/threonine kinase that is a tetramer of two catalytic subunits α and α', and a regulatory subunit β. CK2 plays a critical role in multiple cellular processes such as DNA repair, maintenance of cell viability, protection of cells from apoptosis, and cell-cycle regulation (9, 10). Dysregulation of CK2 plays an important role in cancer progression via regulation of signal transduction pathways, including PI3K/AKT and the MAPK pathway (11, 12). CK2α phosphorylates p53/p21 and increases C-myc, which regulates tumor progression. Furthermore, CK2α overexpression is associated with epithelial-mesenchymal transition (EMT) (13). CK2 overexpression is also correlated with poor prognosis in various cancer types (14, 15). In gastric 6171

Gastric Lavage Malignant Cells (yGL) and Hypohemoglobinemia (yAnemia) as New Systems of Tumor Regression Grading and Prognostic Prediction for Gastric Cancer After Neoadjuvant Treatment

“…patients becomes more complicated and creates confusion even for prognostic prediction (31)(32)(33)(34)(35)(36). With this regard, several reliable tissue and serum markers have already been identified, or are still under investigation, as predictors of the response of GC patients to NAC (13,(16)(17)(18)(37)(38)(39)(40). In our study we suggest 2 further pertinent tests for post-NAC reassessment and prognostic prediction of patients with resectable GC: the yGL and yAnemia clinicopathological features.…”

“…Differing from other gastrointestinal malignancies where multistep carcinogenesis is well-recognized (as for colorectal cancer), to date sporadic GC still has a less known and understood pathobiology (2-6).Surgery still represents the mainstay of therapy but, except for early-stage disease (including early GC; EGC), it cannot assure an effective long-term recovery and must be conducted in concert with peri-operative treatment (7-11). Neoadjuvant chemotherapy (NAC), however, despite initial enthusiasm, has sooner showed conflicting results and limitations against this type of cancer (including gastric and junctional lesions) especially in terms of survival (12)(13)(14)(15)(16).To clarify these doubts, ascertain its role and, consequently, optimize the management of GC patients, recently evaluation of NAC effectiveness has been addressed with several new systems and markers, both theoretical and practical (15)(16)(17)(18). With this purpose, in our study GC patients submitted to NAC were investigated regarding the presence of free malignant cells in their gastric lavage and the development of hypohemoglobinemia, hereinafter referred as yGL and yAnemia, respectively.…”

“…To clarify these doubts, ascertain its role and, consequently, optimize the management of GC patients, recently evaluation of NAC effectiveness has been addressed with several new systems and markers, both theoretical and practical (15)(16)(17)(18). With this purpose, in our study GC patients submitted to NAC were investigated regarding the presence of free malignant cells in their gastric lavage and the development of hypohemoglobinemia, hereinafter referred as yGL and yAnemia, respectively.…”

Circadian rhythms and cancers: the intrinsic links and therapeutic potentials

“…Targeting CK2 with a pan-CK2 inhibitor, BMS-699, resulted in disruption of myeloid cell differentiation and increased efficacy of immunotherapy in mice with lung, colon and breast carcinoma and lymphoma [ 320 ]. Moreover, some potent CK2 inhibitors, such as CX-4945 (silmitasertib) and GO289, have been developed which inhibit the proliferation of several human tumors [ 321 – 323 ]. CX-4945 was the first CK2 inhibitor that entered into clinical trials for the treatment of human tumors [ 324 , 325 ].…”

Casein kinase 2 modulates the spindle assembly checkpoint to orchestrate porcine oocyte meiotic progression

“…Notably, CK2 is overexpressed in cancer cells of the prostate, colon, lung and breast, and takes a critical part in cancer progression by regulating a number of signaling pathways, including PI3K/Akt, Wnt/β-catenin and MAPK [12][13][14]. The anti-apoptotic role of CK2 allows the cancerous cells to escape cell death and continue proliferation, thus becoming an effective drug target for cancer treatment [15,16]. CX-4945, as a first oral bioavailable CK2 small molecule inhibitor, exerts antiproliferative activity in human cancer cells by inhibiting cell cycle and PI3K/Akt signaling pathway [17].…”