Abstract 4787: SKLB188 inhibits the growth of head and neck cancer cell growth by suppressing EGFR signaling

Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. So far, only Cetuximab, an anti-EGFR monoclonal antibody, has been approved for EGFR-target therapy in HNSCC. Here we show that SKLB188, a newly synthesized small molecule compound, inhibited cell proliferation and induced apoptosis of HNSCC cells in vitro and in vivo, by targeting EGFR signaling. SKLB188 induced cell cycle arrest in G 1 phase, by downregulating the expression of Cdc25A, cyclins D1/A and cyclin dependent kinases (CDK2/4), and upregulating the expression of CDK inhibitors (p21 Cip1 and p27 Kip1 ), leading to decreased phosphorylation of Rb. SKLB188 also downregulated the expression of Mcl-1 and survivin, inducing caspase-dependent apoptosis. Molecular docking predicted that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay revealed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC 50 = 5 nM). Western blot analysis showed that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumors. Taken together, our results support that SKLB188 inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signaling. Citation Format: Shile Huang, Mansoureh Barzegar, Shuang Ma, Shengyong Yang. SKLB188 inhibits the growth of head and neck cancer cell growth by suppressing EGFR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4787.