ATM inhibitor M4076 synergizes with ATRis M4344 or M6620 in cancer cells and mouse xenograft models. A, Pairwise analysis of the combination benefit of inhibitors of ATR (M4344, M6620), ATM (M4076), and DNA-PK (peposertib) in a panel of 34 randomly selected cancer cell lines. Cell lines were incubated with drug combinations for 5 days, and their growth and/or viability was determined by the sulforhodamin B assay as described previously (40). Bliss excess was calculated per drug and cell line and plotted (strong synergy >0.1; 0.1≥ weak to moderate additivity/antagonism ≥−0.1; strong antagonism <−0.1). B and C, The combination effect of M4344 and M4076 was evaluated in mice transplanted with MiaPaCa and MV4.11 cancer cells. Mice received subcutaneous injections in the right flank. M4344 (10 mg/kg), M4076 (50 or 100 mg/kg), or the combination thereof were applied orally, once a day throughout the study period, and M4344 was given 1 hour after M4076. Tumor volumes are shows as mean ± SEM (10 mice per group). For MiaPaCa2, P < 0.0001 for vehicle or any of the monotherapy treatment arms and M4076 100 mg/kg + M4344 10 mg/kg.