Cell’s Seven Achilles Heels: Consideration for design of anti-cancer drug
combinations.

shRNA and CRISPR screens are routinely used to identify genes that modulate responses of cells to anti cancer drugs. Here, by integrating GSEA and CMAP analysis of multiple shRNA screens, we uncovered that there is a core set of pathways involved in responses to drugs with diverse mechanisms of action, suggesting that there are “weak points” or “Achilles heels” in a cell, whose mild disturbance can make cells vulnerable to a variety of treatments. These “weak points” pathways include proteasome, protein synthesis, RNA splicing, RNA synthesis, cell cycle, Akt-mTOR, and tight junctions. Accordingly, inhibitors of these pathways might sensitize cells to a variety of drugs. This hypothesis was tested by analysis of the diversity of drugs that synergize with FDA-approved inhibitors of the proteasome, RNA synthesis, and mTOR. Indeed, the quantitative evaluation indicates that inhibitors of any of these pathways can synergize with a more diverse set of pharmaceuticals, compared to inhibitors of pathways distinct from “weak points” pathways. This finding suggests that inhibitors of the “weak points” pathways could be primary candidates in a search for synergistic drug combinations.