ATR inhibition sensitizes CII-ATMsh and Mec1 CLL cells to cytotoxic chemotherapy. CII-shATM (A) and Mec1 (B) cells were treated with chlorambucil, fludarabine, 4-hydroperoxycyclophosphamide (4HC), or bendamustine with or without coadministration of AZD6738 (1 μM). Viability was assessed 96 hours later by the CellTiter-Glo assay. Surviving fraction is expressed relative to untreated controls for chemotherapy treatment alone (no AZD6738) and relative to 1 μM AZD6738 monotherapy for the cotreated samples. Addition of AZD6738 significantly enhanced sensitivity of CII-shATM and Mec1 cells to cytotoxic chemotherapeutic agents. Data are displayed as mean ± SEM of triplicate experiments. Statistical significance was determined using 2-way ANOVA with Bonferroni post hoc analysis. Statistical significance vs no AZD6738 is indicated by *P < .05, **P < .01, and ***P < .001. (C-D) AZD6738 is synergistic with chlorambucil, fludarabine, 4HC, and bendamustine in CII-shATM (C) and Mec1 (D) cells across a range of effective drug doses. Combination indices (CI) were calculated using the median-effect method. Each point represents the mean CI value obtained from 3 independent experiments plotted against the corresponding affected fraction that is expressed relative to untreated controls. CI <0.9 represents synergism, CI = 0.9-1.1 represents additive effect, and CI >1.1 represents antagonism. The actual values are presented in Table 1.