The Ck2 Inhibitor Cx-4945 Enhances The Antitumor Activity Of Egfr-Targeted Agents By Attenuating Signaling In The Pi3k/Akt/Mtor Pathway

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The epidermal growth factor receptor (EGFR) regulates several oncogenic signaling pathways including PI3K/AKT/mTOR, MEK/ERK, and STAT. A number of EGFR antagonists have been approved for treatment of late-stage tumors of epithelial origin. Despite these advances, there are several limitations to these therapies, including primary and acquired resistance, prompting the need to combine EGFR antagonists with agents that target pathways downstream of EGFR. CK2 modulates multiple pro-proliferative and pro-survival signals through many of these same signaling pathways, and co-overexpression of EGFR and CK2 has been frequently observed in solid tumors. Here we present the combination of EGFR-targeted agents with CX-4945, a first-in-class selective CK2 inhibitor currently under evaluation in a Phase I clinical trial. CK2 phosphorylates several key proteins at multiple levels within the PI3K/AKT/mTOR signaling pathway including AKT, PTEN, and p70S6K1. CK2 also regulates the Hsp90/Cdc37 machinery, whose clients include EGFR, AKT, and Src. We proposed that top-down inhibition of EGFR, combined with lateral inhibition of the PI3K/ATK/mTOR pathway by CX-4945, would result in an improved cancer therapy compared to EGFR antagonism alone. This hypothesis was tested in vitro and in vivo in A431 squamous cell carcinoma (SCC) and non-small cell lung carcinoma (NSCLC) models of various genetic backgrounds. Signaling pathways and induction of apoptosis were analyzed by western blot and cell proliferation was measured in a 96-hour cell viability assay. The combination of CX-4945 and erlotinib resulted in enhanced reduction in phosphorylation of AKT (T308), AKT (S473), PRAS40 (S246), mTOR (S2481), mTOR (S2448), p70S6K1 (T389), S6 (S235/6), S6 (240/4), and 4E-BP1 (T37/46), and decreased Mcl-1 levels. These effects were accompanied by decreased cell proliferation and synergistic induction of apoptosis. CX-4945 plus erlotinib exhibited enhanced antitumor activity in A431 SCC and NCI-H2170 NSCLC xenograft models; moreover, in the erlotinib-resistant NCI-H1975 NSCLC xenograft model, CX-4945 plus cetuximab resulted in enhanced efficacy. These data suggest that CX-4945 in combination with EGFR-targeted agents may improve clinical outcomes in patients with EGFR and CK2-driven cancers by inhibiting multiple nodes of the EGFR signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2560. doi:10.1158/1538-7445.AM2011-2560