Abstract LB-69: Targeting CK2 with small molecule CX-4945 modulates NF-kappaB, TP53 and cell survival in head and neck squamous cell carcinoma

Abstract

Abstract Objective: We previously identified CK2 as an upstream kinase activating NF-kappaB and modulating TP53 mediated signaling pathways. Up regulated CK2 activity is implicated in promoting the malignant phenotype and progression of head and neck squamous cell carcinoma (HNSCC). Here, we investigate the antitumor effects of CX-4945, a selective small molecule inhibitor of CK2. Design: The effects of CX-4945 on cell proliferation were measured by MTT assay in a panel of 9 University of Michigan squamous cell carcinoma (UM-SCC) cell lines. The half maximal inhibitory concentration (IC50) was determined in vitro. CX-4945 inhibition of cell cycle and induction of cell death were measured by DNA flow cytometry. The effects of CX-4945 on the activity of NF-kappaB, BCL-XL, and TP53 promoters were tested by the chemiluminescent reporter gene assay. The anti-tumor activity of orally administered CX-4945 was evaluated in SCID mice bearing UM-SCC-11A xenografts. Results: The IC50 in 9 UM-SCC cell lines ranged from 3.4 µM to 11.7 µM. The UM-SCC-11A cell line used for in vivo studies had an IC50 of 4.07 µM in vitro. CX-4945 showed a concentration and time dependent cell cycle arrest in G1 and G2/M phases accompanied by a significant induction of sub-G0 cells indicating cell death. CK2 inhibition with CX-4945 downregulated the reporter activities of survival-promoting genes such as NF-kappaB and BCL-XL and up regulated the reporter activity of apoptosis-promoting gene TP53 in a concentration and time dependent manner. Furthermore, CX-4945 (75 mg/kg) showed significant tumor growth inhibition (31% (p<0.05)) in UM-SCC-11A xenografts compared to the control group. Conclusions: Inhibition of CK2 via CX-4945 reveals anti-proliferative activity and modulation of NF-kappaB activation in HNSCC cell lines. In vivo studies show significant antitumor activity in a bortezomib-resistant HNSCC xenograft model. CK2 is an unexploited target in HNSCC and CX-4945 demonstrates the potential of a therapeutic agent with this novel mechanism of action for the treatment of head and neck cancers. (Supported by NIDCD intramural project ZIA DC-000016) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-69.