Abstract 2687: CK2 inhibitor CX-4945 modulates AKT, NF-kB, TP53 and MEK inhibitor PD-325901 targets AP1 mediated CK2 inhibitor drug resistance in head and neck cancer

Abstract

Abstract We previously identified upregulated kinase CK2 as an activator of NF-B and repressor of TP53 in promoting the malignant phenotype of head and neck squamous cell carcinoma (HNSCC). Here, we investigate the anti-tumor effects of a small molecule CK2 inhibitor CX-4945, alone and in combination with MEK inhibitor PD-0325901 (PD-901), in human HNSCC models in vitro and in vivo. CX-4945 IC50s ranged from 3.4 µM to 11.9 µM in 9 UMSCC cell lines. CX-4945 caused S and G2/M cell cycle arrest, and induced sub-G0 DNA fragments, indicating cell death. CX-4945 inhibited NF-B and BcL-XL prosurvival reporter genes in wild type (wt) TP53 (UMSCC1) and mutant (mt) TP53 (UMSCC46) cell lines, and concurrently upregulated proapoptotic TP53, p21 and prosurvival AP-1 activity only in the wtTP53 cell line. Correspondingly, CK2 phosphorylation of AKT S129 as well as T308 and S473 prosurvival signaling was reduced in both cell lines, but AP-1 inducing p-Erk1/2Thr202/204 was increased in the wtTP53 cell line. In the UMSCC1 xenografts, CX-4945 treatment significantly decreased PI3K/Akt/mTOR pathway signaling by immunostaining. While CX-4945 increased TP53 and TUNEL apoptosis marker staining at early time points (13 days after CX4945 treatment), an opposing increase in p-Erk, FosL1, cJun, JunB, and proliferation (Ki67) were also observed. Consistent with these opposing effects, no significant tumor reduction or improvement in survival was observed by CX-4945 alone. However, combination of CX-4945 with MEK/ERK inhibitor PD-901 exhibited significant synergistic anti-proliferative effects in vitro. Significant anti-tumor effects were observed with MEK inhibitor alone and in combination with CX-4945 in vivo, further supporting a role for MEK/ERK/AP-1 in resistance to CX-4945 in this HNSCC model. Supported by NIH Medical Research Scholars Program and NIDCD intramural projects ZIA-DC-000016, 73 and 74. Citation Format: Yansong Bian, Jiawei Han, Vishnu Kannabiran, Suresh Mohan, Jay Friedman, Kenna Anderes, Zhong Chen, Carter Van Waes. CK2 inhibitor CX-4945 modulates AKT, NF-kB, TP53 and MEK inhibitor PD-325901 targets AP1 mediated CK2 inhibitor drug resistance in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2687. doi:10.1158/1538-7445.AM2014-2687