Figure 4 from Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation

Co-inhibition of PARP and cholesterol biosynthesis pathway improves efficiency in tumor cell killing. A, Viability (ATP levels) of HCC70 triple-negative breast cancer (TNBC) cell line after 7-day treatment with niraparib (6.25 μmol/L) and olaparib (6.25 μmol/L) as a single agent or in combination with LSS inhibitor Ro-48-8071 (300 nmol/L). Mean (n = 3) for four independent biological experiments is shown (linear mixed-effect model with TukeyHSD contrasts, ****, P ≤ 0.0001). Niraparib is more efficient than olaparib in reducing cell viability. Addition of an LSS inhibitor improves both niraparib and especially olaparib efficiency in reducing the viability and makes both inhibitors comparable. B, 3-D surface Bliss synergy response for niraparib–atorvastatin and olaparib–atorvastatin combinations after 7-day treatment in MDA-MB-231 TNBC cell line. Red indicates the region of synergy, and green indicates the region of antagonism. Representative of three independent biological experiments (each n = 3) is shown as well as the mean BSmatrix and P value reported (see Supplementary Fig. S5F and S5G for details including other replicates and statistical analysis). Both combinations with lipophilic atorvastatin resulted in a significant synergistic response (significance criteria: mean BSmatrix > 3, P < 0.05). C, 3D surface Bliss synergy response for niraparib–pravastatin, details as in B. Combination with hydrophilic pravastatin shows no synergy. D, 3D surface Bliss synergy response for niraparib–atorvastatin combination after 7-day treatment in HGS1 (HUB-19-C2-008) patient-derived ovarian cancer organoids (n = 4). This combination resulted in significant synergy (see Supplementary Fig. S5H for details). E, Model: inhibition of PARP combined with inhibition of cholesterol biosynthesis pathway (e.g., through the niraparib off-target activity on LSS or by combination with LSS inhibitors or more strongly with HMGCR inhibitors such as lipophilic statins) can result in increased cell death of tumors subtypes, which depend on steroid metabolism, like TNBC and/or highly metastatic tumors.