Drug repurposing screen targeting PARP identifies cytotoxic activity of efavirenz in high-grade serous ovarian cancer

Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC. In silico ligand-based virtual screening (BLAZE) was used to identify drugs with potential PARP-binding activity. The list was refined by dosing, known cytotoxicity, lipophilicity, teratogenicity, and side effects. The highest ranked drug, efavirenz, progressed to in vitro testing. Molecularly characterized HGSOC cell lines, 3D hydrogel-encapsulated models, and patient-derived organoid models were used to determine the IC50 for efavirenz, cell death, apoptosis, PARP1 enzyme expression, and activity in intact cancer cells following efavirenz treatment. The IC50 for efavirenz was 26.43–45.85 μM for cells in two dimensions; 27.81 μM–54.98 μM in three dimensions, and 14.52 μM–42.27 μM in HGSOC patient-derived organoids. Efavirenz decreased cell viability via inhibition of PARP; increased CHK2 and phosphor-RB; increased cell-cycle arrest via decreased CDK2; increased γH2AX, DNA damage, and apoptosis. The results of this study suggest that efavirenz may be a viable treatment for HGSOC. [Display omitted] Proposed mechanism of action for efavirenz in HGS ovarian cancer. Preclinical data showed efavirenz decreased cell viability via inhibition of activity and expression of PARP1 and PARP2, respectively; increased CHK2 and phosphor-RB expression; increased cell-cycle arrest via decreased CDK2; increased γH2AX and DNA damage; and increased apoptosis.