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
In vitro culture system is a long-standing useful tool in the study of cell biology for developing new therapeutic modalities and discovering new anti-cancer drugs. Therefore establishment and characterization of cell lines are very important in vitro study. However, establishment of GC patients derived cell lines are very challenging, especially with diffuse type which has different biology and worse prognosis from intestinal type. Yonsei Cancer Center (YCC) has been consistently worked to build human cancer cell lines, and resulting in over 30 novel cancer cell lines from metastatic gastric cancer patients. Most of YCC GC cell lines were established by primary culture of peritoneal fluid from metastatic gastric cancer patients. Interestingly, YCC-16 cells were isolated from the peripheral blood of gastric cancer patients. 20 cells were established from diffuse type GC, and 21 cells were from signet ring cell type. In this study, we evaluated 29 YCC GC cell lines and 23 GC cell lines from other sources (ATCC, KCLB, and JCRB). For molecular characterization of 52 GC cell lines, we analyzed copy number variant (CNV), single number variant (SNV) and gene expression using whole-exome sequencing (WES) and RNA sequencing. The 7 cell lines (YCC-17, 18, 19, 20, 29, 34, 36) were compared with their germline variants of paired PBMC. Also, these cell lines were investigated expression of proteins related to cancer progression and the sensitivity of chemotherapies and diverse molecular targeted drugs/antibodies. We evaluated the tumorigenesis with soft-agar assay and invasiveness by transwell assay. In addition to previous novel EBV infected cell line (YCCEL1/YCC-10, J Gen Virol. 2013), we observed amplification and overexpression of receptor tyrosine kinase (RTK) including HER2 (YCC-19, 32, 33, 38, 42), EGFR (YCC-11, 21), Met (YCC-31, 42), and FGFR2 (YCC-28, 30); confirming that protein was overexpression by Western blot in 20/52 (38.5%). Interestingly, amplification of RTKs was detected mutually exclusive pattern with other RTK amplification. Furthermore, RTK amplified cell lines were shown to be sensitive to target specific small molecules such as BGJ398. Also, we identified cell line specific genetic variations including ARID1A which might be the potential new targets in diffuse type GC cell lines. Then we could subgroup the cell lines based on 4 subtypes of TCGA. In conclusion, our GC cell line bank with genomic and biological characteristics based on the clinical information, would be useful in subgroup specific target selection, drug screening and mechanism evaluation for improving GC treatment. Citation Format: Tae Soo Kim, Kyu Hyun Park, Woo Sun Kwon, Won Suk Lee, In Hye Jeong, Sun Kyoung Kang, Hyun Myong Kim, Sun Young Rha, Hyun Cheol Chung. Novel gastric cancer cell lines established from diffuse type gastric cancer patients for potential subgroup-specific therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 139.
Platinum-based antineoplastic drugs are chemotherapeutic agents to usually treat gastric cancer (GC) include cisplatin. However, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Especially, increased DNA repair is drug targetable mechanism and useful in the treatment strategy of cisplatin-resistant cancer. Casein kinase 2 (CK2) has critical role of multiple cellular processes with DNA repair. For this reason, research for CK2 expression correlated with DNA repair mechanism is important in gastric cancer. Combination of cisplatin and CK2 inhibitor (CX-4945, also known as Silmitasertib, Senhwa Biosciences, USA) may improve cisplatin-induced DNA damage for GC treatment. In this study, we screened sensitivity of cisplatin and CX-4945 in 49 GC cell lines by MTT assay. For molecular profiling, we analyzed variants and gene expression using whole exome sequencing and RNA sequencing. RNA and protein expression of CK2 subunits (α/α’) using real-time RT-PCR and Western blot. Also, activity of CK2α was measured by ELISA. Combination treatment performed different schedules including concurrent and sequential. Synergistic effect was analyzed by Bliss Independence model. As CK2 profiling, CK2α’ mRNA expression was a tendency to correlated with CX-4945 sensitivity(p=0.0504). Moreover, CK2α’ protein expression was a correlated with CX-4945 sensitivity(p=0.0252). Other molecular profiling did not reveal any clear correlations. Twenty one (Group1: cisplatin extremely resistant and CK2 high, Group2: cisplatin intermediate resistant regardless of CK2 expression) cell lines were performed combination treatment. Both YCC-21 and YCC-28 cell lines show synergistic effect (+20% and +22%, respectively) in concurrent schedule. Only MKN-74 cell line show synergistic effect (+11%) in Pre-addition. The 4 cell lines (YCC-18, YCC-38, SNU-1 and -216) were show synergistic effect (+10%, +37%, +11% and +19%, respectively) in Post-addition. In conclusion, early inhibition of CK2 shows synergistic effect in group 1, because CK2 is high expression. In group 2, late inhibition of CK2 demonstrated synergistic effect. It means CK2-related DNA repair is up-regulating for repair to cisplatin-induced DNA damage. Personalized the treatment schedule for inhibit CK2-induced DNA repair is a new strategy to restore cisplatin resistant in GC. Citation Format: Hyun Myong Kim, Inhye Jeong, Kyu Hyun Park, Tae Soo Kim, Woo Sun Kwon, Hei-Cheul Jeung, Minkyu Jung, Sun Young Rha. Overcoming cisplatin resistance through the combination treatment with CK2 inhibitor, CX-4945, in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2017-1216
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