Abstract 3788: Drug mechanisms of action: Triangulating with cultured cancer cells

Abstract

Abstract The clinical trial is irreplaceable as a scientific test bed for cancer therapeutics, animal models are becoming ever more sophisticated for preclinical testing, and 3D cell cultures can mimic some aspects of tumor structure and microenvironment. So what are the proper roles of 2D cell cultures in research on mechanisms of drug action? A partial answer is historical: most of our information about mechanisms of drug sensitivity and resistance has come from such cultures. A second is that cells in culture can be engineered readily by selective pressure or genetic manipulation to express or silence any chosen drug target or modulator of drug activity. A third is provided by the emergence of cancer cell panels for use in large-scale drug discovery programs, at the same time generating massive amounts of data that can be used to support or refute hypotheses about molecular mechanism. Cell line assays are not in general predictive of clinical efficacy, but patterns of response among lines and under different conditions can certainly predict mechanism of action, often quite incisively (see, e.g., Weinstein, Science 258;447, 1992). The first large-scale cell-line screen used to illuminate mechanisms of action was the NCI-60, a diverse set of 60 human lines used to test >100,000 compounds and natural products since 1988 (Shoemaker, Prog. Clin. Biol. Res. 2:361, 1988). Because we and others have profiled the same lines at the DNA, RNA, protein, chromosomal, and epigenomic levels (see, e.g., Weinstein, Science 258;447, 1997), it has been possible to correlate molecular aberrations in the cells with their sensitivity to the agents tested. More recently, the Cancer Cell Line Encyclopedia (CCLE) (Barretina, Nature 483;603, 2012) and Cancer Genome Project (CGP) (Garnett, Nature 483;570, 2012) were published, describing molecular profiles and drug response assays for 1,036 cell lines and 24 drugs, and 727 cell lines and 138 drugs, respectively. The three cell panel assays complement each other: the NCI-60 provides a relatively small number of cell types but many tested agents; the CCLE and CGP provide many more cell types but a much smaller collection of tested compounds. Because the assays and experimental conditions being used in the three systems differ (Weinstein and Lorenzi, Nature, doi: 10.1038/nature12839, 2013), we are able to use the similarities and differences in response to ‘triangulate’ for more incisive and extensive information on the robustness of molecular mechanisms suggested by each separately. Even if single pharmacological measurements for a given cell/drug pair show considerable variability across different assay types (Haibe-Kains et al. Nature doi: 10.1038/nature12831, 2013), we find that integrated analysis of the patterns of response across the 60 cell lines and the hundreds of cell lines are often pathognomonic for particular genomic drivers or particular functional pathways. Citation Format: John N. Weinstein, Bo Peng, William C. Reinhold, Yves Pommier, Philip L. Lorenzi. Drug mechanisms of action: Triangulating with cultured cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3788. doi:10.1158/1538-7445.AM2014-3788