the GDSC project at the Sanger Institute 2 and the CTD2 project at the Broad Institute 3) ( Fig. the NCI-60 panel 1), or a modest number of oncology compounds across a large number of cell lines (e.g. Recent efforts, however, have demonstrated the power of large-scale cancer cell line screening – testing either a large number of compounds across a limited number of cell lines (e.g. To date, most oncology repurposing discoveries have been serendipitous systematic, at-scale screening of the entire pharmacopeia has not been feasible.

The prospect of repurposing existing drugs for new clinical indications is alluring: rapid clinical translation can, in principle, occur for drugs already proven safe in humans. These results illustrate the potential of the PRISM drug repurposing resource as a starting point for new oncology therapeutic development. For example, compounds that kill by inducing PDE3A-SLFN12 complex formation vanadium-containing compounds whose killing is dependent on the sulfate transporter SLC26A2 the alcohol dependence drug disulfiram, which kills cells with low expression of metallothioneins and the anti-inflammatory drug tepoxalin, whose killing is dependent on high expression of the multi-drug resistance gene ABCB1. Follow-up of several of these compounds revealed novel mechanisms. Moreover, the killing activity of the majority of these drugs was predictable based on the molecular features of the cell lines. We found that an unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines. Relative barcode abundance following treatment thus reflects cell line viability.

To accomplish this, we used PRISM, which involves drug treatment of molecularly barcoded cell lines in pools. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. Anti-cancer uses of non-oncology drugs have been found on occasion, but such discoveries have been serendipitous and rare.

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