This GW786034 is the same methodology underlying the SPIED database. We took the responder profiles for the 1,218 drugs and searched the SPIED for maximally correlated expression change profiles. The objective is to see to what extent the CMAP transcriptional signatures correlate with transcriptional responses assimilated within our platform independent database of over 100,000 microarrays deposited by a very large number of groups to the public domain. The CMAP is well populated with drugs that target the same or different steps in the PI3K mTOR signalling cascade. In this context the results for LY 294002, rapamycin and wortmannin showed a high degree of overlap, see additional file 1 for the full fold change data. It is a straightforward matter to query the SPIED with these drug expression profiles.

This is done by calculating the regression scores against the individual SPIED entries and retaining the top 100 correlations, see Methods for details. For simplicity and uniformity of treatment, unless otherwise stated, we query SPIED with expression profiles containing 500 genes with the largest fold values passing the p 0. 05 significance threshold. It should be noted that results will be largely insensitive to the size of the query profile. The top SPIED correlate for all three drugs was the Pan PI3K inhibitor GDC 0941 treated T47D breast can cer cells and the regression scores for the tree query sig natures against all 6 samples in the series are shown in Figure 1A. The high degree of correlation is illustrated by regression plots for the three query profiles against the pooled GDC 0941 profile, see Figure 1B, C, D.

All three inhibitor queries also pick out mTOR antagonist studies, but a more interesting correlation is with a glucocorticoid Anacetrapib treatment of acute lym phoblastic leukaemia cells, the rapamycin scores are shown in Figure 2A. The correlation increases with the length of drug treatment, being higher at 24 hours, Figure 2B, C. This result reveals another connec tion between mTOR antagonism and the corticosteroid mechanism as it has been shown that corticosteroid resistance in ALL can be overcome by mTOR antagon ism. Chronic myeloid Leukaemia and some instances of ALL are the result of the ABL tyrosine kinase translocation and fusion to BCR, the BCR ABL fusion event. This pathology has been targeted with rapamycin and our results support this approach based on the high degree of anti correlation of the CMAP rapamycin profile with a transcriptional profile of BCR fusion construct transformed chord blood cells. The correlation scores are shown in Figure 3A. There is a clear anti correlation of rapamycin profile with the BCR ABL profiles pointing to a possible reversal of the phenotype, Figure 3B.