A model for synthetic lethality in CLL cells with ATM or p53 deficiency by inhibition of ATR. ATM and ATR are master regulators of DDR, with ATM being activated in response to DNA double-strand breaks, and ATR in response to replication stress. (A) Activation of the ATR pathway leads to cell cycle arrest mediated primarily through the G2/M checkpoint and repair of stalled replication forks. This leads to the resolution of replication stress. (B-C) Inhibition of ATR by AZD6738 directly induces replication stress by slowing and stalling replication forks. The inability of CLL cells to resolve stalled forks as a result of suppressed ATR signaling leads to collapse of stalled replication forks into fragmented, partially replicated sister chromatids with free DNA DSEs that necessitate repair through the ATM/p53 pathway. This involves cell cycle arrest mediated primarily through the G1/S checkpoint and HRR. (D) In cells with defective ATM or p53, inhibition of ATR by AZD6738 results in an intolerable accumulation of unrepaired DNA damage. This arises from impaired HRR because of defective ATM and/or impaired cell cycle regulation resulting from combined loss of functional ATR and ATM/p53. PCNA, proliferating cell nuclear antigen; Polε, DNA polymerase ε.