Abstract 2427: The difference of drug sensitivity between HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines

Abstract

Abstract Objectives: Infection with the human papillomavirus (HPV) is an important risk factor for development of head and neck squamous cell carcinoma (HNSCC). Strikingly, HPV-positive HNSCCs carry a more favorable prognosis and are a biologically distinct subgroup when compared with their HPV-negative counterparts. We aimed to discover novel therapeutic targets by conducting a high-throughput drug screening platform in vitro with both FDA approved and investigational drugs. Based on our prior proteomic analysis we tested inhibitors of pathways activated in HPV+ HNSCC tumors. Methods: Cell viability assays were performed by the Cell Titer Glo method in a panel of 66 fingerprinted HNSCC cell lines using 13 drugs at concentrations of 0.011 to 9.613 μM. This panel includes 9 HPV+ lines and 57 HPV- lines (5 oropharynx, 15 oral cavity, and 37 others). The IC50 values were calculated. Western Blot assay was used to confirm that the drugs inhibited their targets. Results: We observed a wide range of sensitivities to all 13 drugs with the exception of BKM120 which was effective in all tested lines (Table 1). In contrast, nearly all cell lines were resistant to BMN673, ruxolitinib, LEE011, and selicilib. The HPV+ cell lines were more sensitive to MEK162 (p<0.05) and resistant to Bosutinib (p<0.01) when compared to the HPV- HNSCC cell lines or oropharynx and oral cavity cell lines (Table 2). Western blotting confirmed target inhibition for the targeted therapies. Conclusions: For most agents tested, HNSCC cell lines displayed similar drug sensitivity regardless of the tumor site. However, HPV+ lines were more sensitive to MEK162 and more resistant to Bosutinib. Future analysis will include comparing drug sensitivity to mutation, gene and protein expression in these lines. Taken together, the results may provide a rationale for the clinical evaluation of MEK inhibitors as a molecular targeted approach for the treatment of HPV+ HNSCC. Table 1. IC50 values in 66 HNSCC cell lines DrugDrug's targetMedian IC50 (μM)Range of IC50(μM)Cmax (μM)ErlotinibEGFR5.970.12- >9.614LEE011CDK4/69.610.01- >9.61NABKM120PI3K0.640.01- >1.434MEK162MEK9.610.01- >9.611BosutinibSrc2.320.19- >9.610.8SeliciclibCDK2/59.610.01- >9.619.02VolasertibPLK1.120.01- >9.611.2AZD7762CHK1/20.120.02- >3.02NADocetaxelChemotherapy9.610.01- >9.610.08CisplatinChemotherapy8.620.01- >9.617.33RuxolitinibJAK9.610.01- >9.611.48AZD1775Wee10.250.03- >7.521.65BMN673PARP9.610.20- >9.610.07 Citation Format: Ming Zhang, Tuhina Mazumdar, Shaohua Peng, Pan Tong, Vaishnavi Sambandam, Lauren A. Byers, Jeffrey N. Myers, Jing Wang, Faye M. Johnson. The difference of drug sensitivity between HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2427. doi:10.1158/1538-7445.AM2015-2427