FIGURE 2.

Potential models of action of ataxia telangiectasia and Rad3‐related inhibitors (ATRis) depending on DNA replication stress (RS) levels. Because their RS stems from a high rate of DNA replication and/or genomic instability, cancer cells often have an increased reliance on the ATR signaling pathway compared with normal cells, conferring susceptibility to therapeutic approaches using ATRis. Cancer cells harboring oncogene activation and/or DNA damage response defects survive with low levels of RS and might require high doses of ATRis to reach the RS threshold that induces cell death. When cancer cells acquire ATR‐mediated RS tolerance, they are more dependent on ATR signaling for survival. In addition, cancer cells treated with RS‐inducing drugs exhibit high levels of RS that synergize with low doses of ATRis to induce cell death. Finally, RS at levels over the threshold, induced by ATRis, can lead to cell death through replication catastrophe in early S cells and mitotic catastrophe in late S to G2/M phase cells.