American Association for Cancer Research
crc-23-0193_fig2.png (992.31 kB)

FIGURE 2 from Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs

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posted on 2023-08-25, 14:20 authored by Thomas S. Dexheimer, Nathan P. Coussens, Thomas Silvers, John Wright, Joel Morris, James H. Doroshow, Beverly A. Teicher

Combination of PARP inhibitors and temozolomide. A, Mean Bliss matrix scores were calculated from each combination's concentration matrix [(5 concentrations of drug A) × (6 concentrations of drug B) = (30 combination concentrations)]. The scores (n = 546) are graphed for all combinations of DNA-damaging drugs with DNA repair inhibitors tested (n = 21) in all complex tumor spheroid models (n = 26). B, The same data shown in A) but combinations of the DNA-damaging drug temozolomide with either PARP inhibitor olaparib or talazoparib are highlighted in blue (n = 52), whereas all other combinations are shown in light gray. C, A scatter plot of the mean Bliss matrix scores from the temozolomide combinations with olaparib and talazoparib (Pearson r = 0.73, two-tailed P < 0.0001). Concentration–response curves (top, mean ± SD, n = 4 technical replicates) from combinations of temozolomide with either olaparib (D) or talazoparib (E) and corresponding mean Bliss score plots (bottom, n = 4 technical replicates) showing the scores from each combination's concentration matrix and colored as a heat map (blue indicates synergy; yellow indicates additivity; red indicates antagonism). Data are shown for complex tumor spheroids grown with the malignant cell lines (from left): VA-ES-VJ (epithelioid sarcoma), SYO-1 (synovial sarcoma), 287954-098-R-J1 (Ewing sarcoma), 349418-098-R (NSCLC), and DMS 114 (SCLC).



Clinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.