Fig. 3: Defects in the Shieldin complex cause PARP inhibitor resistance but Polθ inhibitor synthetic lethality.
From: Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
a Survival curves of RPE1.BRCA1wild-type or RPE1.BRCA1‒/‒ cells exposed to ART558 for 7 days. Cell viability was estimated by CellTiter-Glo. Data are mean surviving fractions (SF) ± SD, n = 3. Two-way ANOVA with Sídák post hoc test was used to calculate p values. b Bar plots illustrating SF of RPE1.BRCA1wild type or RPE1.BRCA1‒/‒ exposed to DMSO, 0.1 μM olaparib, 0.5 μM ART558 or olaparib/ART558 for seven days. Data are n = 2. c Area under the curve of dose–response ART558 survival curves in BRCA1 wild type or mutant cell lines. Cell viability was estimated by CellTiter-Glo reagent after 5 days drug exposure. Data are mean SF ± SD, n = 3. d Overview of breast tumour organoid isolation culture and BRCA1 mutation. e Overview of breast tumour organoid culture. e, f Dose–response survival curves of breast tumour organoid cultures exposed to ART558 (e) or olaparib (f) for 14 days. Cell viability was estimated by CellTiter-Glo. Data are mean SF ± SD, n = 3. g Drug Effect Z-scores for ART558 or h olaparib chemosensitisation screen in RPE1 BRCA1‒/‒ or RPE1 BRCA1Wild-type cells. i Dose–response survival curve for MDA-MB-436 cells (parental), two SHLD2-defective clones (dotted lines) or two SHLD2-defective clones with restored SHLD2 expression. Data are mean SF ± SD, n = 3. Two-way ANOVA with Sídák post hoc test was used to calculate p values (j). Therapeutic response to ART812 in rats bearing established MDA-MB-436 BRCA1 mutant, SHLD2‒/‒ xenografts. Animals were treated over 76-days with either drug vehicle (n = 7) or ART812 (100 mg/kg, n = 7). ****p = <0.0001 (two-way ANOVA with Sídák multiple comparison test). k Tumour volume measurement at the end of study. ****p = <0.0001 (two-way ANOVA with Sídák multiple comparison test). l Dose–response survival curve for wild-type, Brca1∆11, Trp53bp1‒/‒ or Brca1∆11Trp53bp1‒/‒ MEF cells exposed to ART558 for 14 days. Cell viability was estimated by CellTiter-Glo reagent. Data are mean SF ± SD, n = 3. Two-way ANOVA with Sídák post hoc test was used to calculate p values. m ART558, olaparib and carboplatin survival curves in a prostate cancer patient-derived organoid culture. PR6512 (see Supplementary Fig. 2i, j). Data are mean SF ± SD, n = 3.
