Abstract #4702: Pathway-based comparison approach for the identification of responders to the mitotic modulator ON 01910.Na in head and neck cancer (HNC)
Authors: Aik Choon Tan, Ryan Anderson, Barbara Frederick, David Raben, Antonio Jimeno
Journal: Cancer Research (2009)

Purpose: This work is aimed at determining the efficacy of the novel clinical stage mitotic inhibitor ON 01910.Na in HNC, and to elucidate gene expression-based predictors of efficacy, in comparison with approved therapeutic agents. We used a rational pathway-driven comparison of global gene expression (Affymetrix U133) to correlate changes in expression with efficacy. Methods: We used 29 HNC cell lines and tested ON 01910.Na and a panel of 10 approved agents (including cetuximab, erlotinib, docetaxel and bortezomib). We then correlated the antitumor efficacy with gene expression profiles of these cell lines, using unbiased gene set expression analysis (GSEA; www.broad.mit.edu/gsea/) of 198 pathways. GSEA permits elucidating modest but coordinated gene expression differences at the pathway level. Results: We obtained a mosaic of susceptibilities in the panel. At clinically relevant concentrations (1 uM) docetaxel, bortezomib and ON 01910.Na significantly inhibited growth in 27, 27, and 25 cell lines respectively, whereas only 9 were inhibited with erlotinib and only two by cetuximab. Expression analysis for ON 01910.Na indicated that at 0.1 microM, the \#8220;cell cycle pathway\#8221; was the tenth most expressed gene set in comparing the sensitive vs resistant cell lines, whereas the \#8220;p53 pathway\#8221; was the most highly expressed in resistant vs sensitive strains. At 1 uM, the \#8220;cell cycle\#8221; pathway was the most differentially expressed pathway in comparing sensitive vs resistant cell lines. Of the 98 genes in the \#8220;cell cycle\#8221; pathway, those acting as \#8220;driver\#8221; genes included CHEK1, CCNE2, CDC6, CDC7, SMAD4, and CCND2. The analysis of bortezomib showed that the \#8220;proteasome\#8221; pathway was the fifth most expressed of 198 pathways in sensitive vs resistant. Similar analysis with docetaxel indicated that pathways over-expressing cytoskeleton components were particularly expressed in sensitive strains. Conclusions: ON 01910.Na is a highly effective mitotic inhibitor active in a broad panel of HNC cell lines, with potentcy equivalent or superior to approved agents. Expression analysis revealed that sensitive strains had over-expression of the cell cycle pathway (providing further evidence of mechanisms relevant in the action of ON 01910.Na in HNC). The only four resistant cell lines shared over-expression of the p53 pathway as the leading expression alteration. The \#8220;cell cycle\#8221; pathway changes were drug dose dependent. Overall this suggests that cells with a de-regulated cell cycle are more sensitive to ON 01910, and that a functional p53 pathway dictates resistance. These results combined with the observations with established therapeutic agents suggest that pathway comparisons provide a rational method for identifying targets for new drugs and biomarkers for personalized therapy. Complete pathway expression profiles for all drugs tested and in vivo data will be presented.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4702.