Abstract 417: Integrative drug sensitivity analysis of PI3K /mTOR pathway inhibitors in Head and Neck Squamous Cell Carcinoma (HNSCC)

Abstract

Background: HNSCC is the sixth most common cancer worldwide. To date, Cetuximab is the only approved targeted therapy for HNSCC treatment. Thus,there is an immediate need to discover effective targets. Two pharmacogenomic HTS studies, Cancer Genome Project (CGP) and Cancer Cell Line Encyclopedia (CCLE) provide a large repository of drug sensitivity data. The PI3K/mTOR pathway is one of the frequently activated signaling cascades in HNSCC. However, it is unclear which class of PI3K/mTOR inhibitors is most promising and which biomarkers may be used to predict sensitivity. The rationale for this study is to identify novel biomarkers to targets such as PI3K/mTOR pathway by data mining these public databases. The potential biomarkers will be characterized in vitro in 68 HNSCC cell lines.Methods:The landscape of drug sensitivity profiles in 23 HNSCC cell lines (CGP) was analyzed by boxplot illustrations. Drugs that induce growth inhibition at low doses (median≤10 μM) were considered “effective”. Chemotherapy drugs, drugs with missing values and unknown targets were excluded from analyses. Hierarchical clustering of cell lines was performed based on drug sensitivity using GOWER distance metric and Ward's linkage after normalization. Clustering of 140 drugs based on their sensitivity profiles was also done. In vitro, drug response to PI3K pathway inhibitors in 28 HNSCC cell lines was assessed by ATP based cell viability assay (CellTiter-Glo). Results: In the CGP datasets, we identified a set of effective drugs with median IC75<10 μM. These include drugs targeting HDAC, HSP, BCL2 and CHK1/2, and PI3K/mTOR pathway. When hierarchical clustering of drugs based on drug sensitivity was performed, 3 clusters were classified. Predictably, chemotherapy agents clustered together. Selective drugs that were effective in a subset of cell lines were also identified. To identify cell lines that were uniformly sensitive to inhibitors targeting the PI3K/mTOR pathway, diverse classes of inhibitors targeting PI3K pathway were selected and drug sensitivity was analyzed across 28 HNSCC cell lines. Notably, all cell lines were sensitive to the pan Class I PI3K inhibitor, BKM120 (IC75 <Cmax: 1.68 μM). We identified seven lines that were resistant and twelve lines that were sensitive to different PI3K/mTOR inhibitors. To identify novel biomarkers of sensitivity, we will use Reverse Phase Protein Array (RPPA), exome sequencing and gene expression data on cells that are uniformly sensitive and resistant to PI3K pathway inhibition. Conclusion: HNSCC cell lines were sensitive to a broad range of targeted therapies in in vitro screens including several inhibitors of the PI3K/mTOR pathway. We independently confirmed sensitivity to similar inhibitors and identified lines that were universally sensitive and resistant to this class of drug for biomarker development. Citation Format: Vaishnavi Sambandam, Li Shen, Ming Zhang, Rishi Saigal, Lauren A. Byers, Curtis Pickering, Jeffrey N. Myers, Jing Wang, Faye M. Johnson. Integrative drug sensitivity analysis of PI3K /mTOR pathway inhibitors in Head and Neck Squamous Cell Carcinoma (HNSCC). [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 417. doi:10.1158/1538-7445.AM2015-417