Clinical inhibitor of the ATR pathway consistently resensitizes SLFN11-deficient cells to clinical DNA damaging agents. (A–C, Upper) DU145 SLFN11-WT and -KO cells were treated with M4344 (25 nM) and the indicated concentrations of the TOP1 inhibitors CPT, TPT, and indotecan (LMP400) for 72 h. Cell viability was analyzed by CellTiter-Glo. Error bars represent SD (n = 3). (Lower) Combination Index (CI) versus Fa (fraction affected) calculated from cell viability data. (D) Combination treatment of M4344 (1 nM) and the indicated concentrations of CPT in the isogenic WT and SLFN11-KO leukemic lymphoblasts CCRF-CEM cells. (E) Combination treatment of M4344 (25 nM) and the indicated concentrations of CPT in small-cell lung cancer DMS114 cells. (F–H) DU145 cells were treated with M4344 (25 nM) and the indicated concentrations of etoposide, talazoparib, and cisplatin for 72 h. Cell viability was analyzed by CellTiter-Glo. Error bars represent SD (n = 3).