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Targeting Cancer Cells by Exploiting Karyotypic Complexity and Chromosomal Instability
We have completed a detailed analysis of the chromosomal aberrations present in the drug-discovery panel of 60 human cancer cell lines (the NCI-60), used by the NCI Developmental Therapeutics Program (DTP) to screen compounds for anticancer activity (Roschke AV et al. Cancer Res 63: 8634–47, 2003). Measures of karyotypic complexity include the number of clonal chromosomal rearrangements present in a cell line (structural complexity), the number of chromosome deviations from the ploidy level (numerical complexity), and modal chromosome number. Measures of cell-to-cell chromosomal variability, which reflect the degree of ongoing instability, include numerical and structural heterogeneity. The NCI-60 cancer cell lines show wide variation in these parameters. Karyotypes of these cell lines have been made publicly available on two Web sites (http://www.ncbi.nlm.nih.gov/sky/skyweb.cgi and http://home.ncifcrf.gov/CCR/60SKY/new/demo1.asp). We then looked for relationships between markers of the chromosomal state and drug resistance or sensitivity. As a first snapshot, we used a 1,429-drug subset of the more than 100,000 compounds tested against the cell lines in a short-term cytotoxicity assay. This subset was selected because each agent had been tested at least four times on all or most of the NCI-60. It includes most of the drugs currently used clinically for cancer treatment, along with many candidates that have reached clinical trials. A correlation analysis was performed comparing sensitivity data (expressed as the negative logarithm of GI50 [growth inhibition of 50%]) and each of the karyotypic parameters. A positive correlation between sensitivity to a given compound and an increased level of a given karyotypic parameter means that cell lines with higher values for that specific parameter would be more sensitive to the growth inhibitory action of that agent. The positive correlations between drug sensitivity and karyotypic complexity and heterogeneity found in this analysis (122 statistically significant positive correlations, P < 0.05) allowed us to identify agents that are more active against karyotypically complex and chromosomally unstable cancer cells. Grouping of selected agents based on their functional classification or chemical structure yielded seven distinct groups of chemical compounds. Relationships between karyotypic parameters and sensitivity of cancer cells to identified classes of agents are diagrammed in Figure 1. Figure 1. Stratification of compound groups based on activity associated with a particular karyotypic parameter. NC, numerical complexity; NH, numerical heterogeneity; SC, structural complexity; SH, structural heterogeneity. To explore the possibility that an agent targeted a particular cell lineage that just happened to be more karyotypically complex or that other cellular “states,” such as mismatch repair status or p53 gene status, might be the critical factors acting as determinants of sensitivity or resistance to these compounds, we reanalyzed the data for selected compounds from each group. We did this sequentially, leaving out one and then another of each of the nine lineages in the panel, or leaving out the six mismatch repair-defective cell lines or the 18 p53 wild-type cell lines present in the panel. The essential features of the correlations that we described and the groups of compounds that we identified were not changed by these additional tests. In collaboration with David G. Covell, PhD, Anders Wallqvist, PhD, and Ruili Huang, PhD (Screening Technologies Branch, NCI), we performed a much larger-scale correlation analysis of karyotypic parameters using data obtained from approximately 30,000 chemical compounds tested on the NCI-60 cell lines, and identified additional classes of chemical agents associated with karyotypic parameters (Wallqvist A et al. Mol Cancer Ther 4: 1559–68, 2005). As an aid to this analysis, we employed computational tools based on methods of self-organizing maps (SOMs) used by the Covell lab to cluster the NCI’s database of GI50 measurements of these 30,000 compounds across the panel of NCI-60 cancer cell lines (http://spheroid.ncifcrf.gov). When we made projections on these maps of the compounds that have been identified as positively and significantly correlated with karyotypic parameters, they mainly hit a relatively unexplored region in the SOM, where standard anticancer drugs are not, for the most part, present, and where mechanisms of action of chemical compounds are among the least elucidated. These findings suggest that these “lead” compounds identified as active against karyotypically complex and/or chromosomally unstable cancer cells may, indeed, represent new classes and mechanisms of action for potential anticancer agents. The karyotypic parameters associated with the activities of these compounds may well be markers for underlying genes or pathways that are the true targets of these agents. It is equally important, however, to recognize that certain agents may be active against the “state” of complexity or instability itself rather than against any specific gene product or pathway. It is plausible that the assessment of the chromosomal state of a cancer cell population could serve as a future guide for the selection of drugs active against aggressive and intractable cancers.
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ost cancers have an abnormal chromosomal content, called aneuploidy, characterized by changes in chromosomal structure and number. Chromosomal aberrations tend to be more numerous in malignant tumors than in benign ones, and karyotypic complexity is associated with poorer prognoses and aggressive clinical and distinctive histopathologic features. Therefore, quantitative or qualitative changes in the karyotypic state of malignancy could represent determinants for anticancer therapies and might ultimately allow targeting of the most aggressive and incurable cancers.