Fig. 5: Synthetic lethality by drugs repurposed as DSB repair pathway outcome inhibitors.

a Schematic of synthetic lethality of DSB repair pathways. DNA DSBs can be utilized to kill cancer cells that carry a genetic deficiency in DSB pathways when also provided with matching DSB pathway inhibitor drugs. b Percentage of top ten frequently mutated DNA repair genes in common cancers from the COSMIC database (data from Chae et al.⁶¹). Genes involved in HDR, MMEJ, and NHEJ are shaded green, purple, and blue, respectively. c Dose-response curve of surviving fraction of cells for treatment of 409B2 hiPSCs or Capan-1 cells with the DSB-inducing drug cisplatin for 5 d. The respective EC75 (concentration that induces 25% cell death) is stated. d Dose-response curves of surviving fractions in wild type (grey) and PRKDC-inactivated 409B2 hiPSCs (blue), with (dashed lines) or without (solid lines) cisplatin treatment for 5 days. Sigmoidal fits are shown as lines. e Dose-response curves of surviving fractions in wild type 409B2 hiPSCs (grey) and BRCA2-inactivated Capan-1 cells (green), with (dashed lines) or without (solid lines) cisplatin treatment for 5 days. Sigmoidal fits are shown as lines. f Relative survival of BRCA2-corrected (grey) and BRCA2-inactivated (green) Capan-1 cells treated with drugs for 14 days, compared to the solvent control. g Genome editing efficiencies of correction of the DNA-PKcs K3753R mutation back to the wild type state using CRISPR Cas9-HiFi RNP editing in 409B2 hiPSCs and subsequent culturing in media containing no drug, artemether, or raloxifene. For corrected cells (pink), replicates are depicted by dots. Independent biological replicates were performed (n  =  4 for c; n = 3 for d–f; n = 2 for g). Error bars show the s.e.m. Source data are provided as a Source data file.