biostudies-literatureUnknown4(9)Rutkowska AAn in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyziCancer research communications2427-2443https://www.ebi.ac.uk/biostudies/studies/S-EPMC11403291biostudies-literatureSynergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation.PMC11403291Duempelfeld BBraun FGade SFufezan CFeng BPetretich MAlvarado DPocha SGrandi PSweetman GMARemlinger KColeman KDvornikov DWang ZSchofield CFaelth-Savitski MJansson KHKeles HCurry ESharma GWerner TReddington JPMartinez-Segura AHennrich MLKarpiak JBantscheff MRutkowska AStronach EASevin DCEberl HCBergamini GfalseSynergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation.An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyzi2024-01-01T00:00:00Z2024 Sep2026-07-15T04:52:36.537Z2025-04-06T16:09:31.623ZS-EPMC114032913902893210.1158/2767-9764.CRC-23-0549