Abstract LB-120: Large-scale cancer cell line screening with a novel and selective HDAC-6 inhibitor (ACY-1215) identifies candidate predictive biomarkers for breast cancer.

Abstract

Abstract ACY-1215 is a novel and selective inhibitor of HDAC6 currently in Phase 1 clinical trials in combination with bortezomib (Velcade) or lenalidomide (Revlimid) in relapsed/refractory multiple myeloma. Inhibitors of HDACs have demonstrated potent anti-cancer activity mediated by increased levels of acetylation of both histone and non-histone proteins, resulting in growth arrest, cell differentiation and apoptosis. In the present work, the broader anti-tumor activity of ACY-1215 was investigated with a panel of 65 human tumor cell lines derived from the major cancer types, to define additional oncology indications for clinical development and to identify candidate biomarkers of tumor sensitivity and drug resistance. A group of 14 breast cancer cell lines was used to identify potential predictive biomarkers based on the wide range of sensitivity to ACY-1215 allowing robust correlation analysis. A panel of 42 genes was identified based on cellular sensitivity to ACY-1215 (IC50 values) correlating to gene expression levels and underlying genetic mutations in the individual cell lines as reported in the Cancer Cell Line Encyclopedia (CCLE). The Reactome “Functional Interaction Cytoscape Plugin” was used to partition these signatures genes into cancer-associated networks, which included the PIK3R2, ERBB2/STAT3, and TGFB3 signaling pathways. Association with these pathways and potential mechanism of action is consistent with observed synergistic anti-tumor activity between ACY-1215 and PI3K inhibitors. Also Gene Set Enrichment Analysis (GSEA), correlating ACY-1215 sensitivity with gene expression levels, revealed significant over-representation of genes in the p53 pathway, and pathways regulating cytoskeletal structure, cell adhesion, cell cycle and proliferation. A subset of these results support the proposed cytotoxic activity of selective HDAC6 inhibition through blocking of cell motility and misfolded protein clearance, while other findings suggest further novel pathways affected by inhibition of HDAC6. Confirmation of predicted sensitive and resistant cell lines using the gene signatures will lead to the development of predictive biomarkers and selection of tumor type(s) for in vitro and in vivo validation with ACY-1215 in combination with novel and approved standard of care therapeutics. Citation Format: Min Yang, David Tamang, Simon S. Jones, Lie Di. Large-scale cancer cell line screening with a novel and selective HDAC-6 inhibitor (ACY-1215) identifies candidate predictive biomarkers for breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-120. doi:10.1158/1538-7445.AM2013-LB-120