Induction of synthetic lethality in hematologic malignancies with DDR inhibitors. DDR defects and oncogene activation associated with the BRCAness phenotype confer sensitivity to the inhibition of PARP proteins that participate in alternative DNA repair pathways. DDR defects and the BRCAness phenotype also compromise DNA replication, leading to replication stress. ATR, a principal regulator of replication stress response, is activated by the single-stranded (ss) DNA-RPA complex, which forms rapidly after the exposure of ssDNA at stalled replication forks. The ATR effector kinase CHK1 induces the S-phase cell cycle checkpoint and activates WEE1 kinase to induce the G2-M cell cycle checkpoints. CHK1 also regulates replication origin firing and timely S to G2 transition. Normal ATR/CHK1 function (in green) prevents replication fork collapse, exacerbation of replication stress (in purple), and early S/G2 transition before replication is successfully completed. ATR, CHK1, or WEE1 inhibition therefore results in uncontrolled cell cycle progression despite replication stress, leading to mitotic catastrophe and apoptosis.