Figure 3.

Specific synergistic activity of PARPi combination therapies in H3G34R_ATRX patient-derived cell and iPSC models. (A) Schematic representation of a circular synergy dot-plot showing mean combination indices (CI) values. The small inner circle depicts synergistic CI values (<0.9). The middle circle represents additive CI values (0.9–1.1) and CI values >1.1 are considered antagonistic (white circle). Antagonistic CI values > 2.1 are collected in the light violet circle boundary. CI values were determined with CalcuSyn. CI < 0.9, synergism; CI = 0.9–1.1, additive effects; or CI > 1.1, antagonism. Each quarter represents one concentration of the PARPi and within each quarter increasing doses of the combined drug are shown. (B-E) Circular synergy dot-plots for niraparib in combination with topotecan (B-C), talazoparib with either ceralasertib (D) or AZD-7762 (E) are presented. Mean CI values based on the cell viability data of patient-derived pHGG cell models were calculated from n = 3 independent experiments. In case of VBT125 and VBT347 topotecan concentrations are 0.005; 0.025; 0.05 and 0.075 µM. (F) Circular synergy dot-plots for niraparib in combination with topotecan in H3.3 G34R OE and H3.3 G34R OE_ATRX KO iPSCs. Mean CI values based on the cell viability data of iPSC models were calculated from n = 3 independent experiments.