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. Author manuscript; available in PMC: 2023 Nov 17.
Published in final edited form as: Mol Cancer Res. 2023 Oct 2;21(10):1017–1022. doi: 10.1158/1541-7786.MCR-22-1035

Figure 2.

Figure 2.

Targeting Polθ + PARP and Polθ + RAD52 induced dual synthetic lethality against HR-deficient leukemia cells. A, Western blot analysis showing the expression of indicated proteins in the nuclear fractions of Nalm6(RAD54+/+) and Nalm6(RAD54−/−) isogenic cell lines. B, HR activity in Nalm6(RAD54+/+) and Nalm6(RAD54−/−) cells: results represent mean % SD of GFP+ cells in RFP+ cells. Nalm6(RAD54+/+) and Nalm6(RAD54−/−) cells were treated for 72 hours (C) and 12 hours (D) with 25 mmol/L Polθi ART558, 2.5 nmol/L PARPi talazoparib, 10 mmol/L RAD52i 6-hydroxy-DL-dopa and the indicated combinations. Results show mean number SD of colony numbers (C) and mean % of tail DNA SD (D). E, Western blot analysis showing the expression of indicated proteins in the nuclear and cytosolic fractions of HEL cells with tet-inducible IDH1wt or IDH1(R132H) mutant. F, HR activity in HEL cells expressing IDH1wt or IDH1(R132H) mutant: results represent mean % SD of GFP+ cells in RFP+ cells. HEL cells expressing IDH1wt or IDH1(R132H) mutant were treated for 72 hours (G) and 12 hours (H) with 25 mmol/L Polθi ART558, 1 mmol/L PARPi olaparib, 2.5 mmol/L RAD52i 6-hydroxy-DL-dopa and the indicated combinations. Results show mean % SD of colony numbers when compared with untreated cells (G) and mean % of tail DNA SD (H). I, HR activity in Lin-CD34+ cells from HR-proficient and HR-deficient AMLs (n = 3 of each). Results represent mean % SD of GFP+ cells in RFP+ cells. J, Lin-CD34+ cells from HR-proficient and HR-deficient AMLs (n = 3 of each) were treated with 25 mmol/L Polθi ART558, 1.25 mmol/L PARPi olaparib, 2.5 mmol/L RAD52i 6-hydroxy-DL–dopa and the indicated combinations. Results represent mean % SD of colonies in comparison with untreated cells. K, Survival curves of the AML mice treated with vehicle (C), Polθi RP6685, PARPi olaparib, and the combination. (B–D and F–J) Statistical significance when compared with: # another group, + control, and * corresponding individual treatments. K, ***, P < 0.001 in comparison to other groups.