Figure S5 from Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation

Rutkowska, Anna; Eberl, H. Christian; Werner, Thilo; Hennrich, Marco L.; Sévin, Daniel C.; Petretich, Massimo; Reddington, James P.; Pocha, Shirin; Gade, Stephan; Martinez-Segura, Amalia; Dvornikov, Dmytro; Karpiak, Joel; Sweetman, Gavain M.A.; Fufezan, Christian; Duempelfeld, Birgit; Braun, Florian; Schofield, Christopher; Keles, Hakan; Alvarado, David; Wang, Zhuo; Jansson, Keith H.; Faelth-Savitski, Maria; Curry, Edward; Remlinger, Katja; Stronach, Euan A.; Feng, Bin; Sharma, Geeta; Coleman, Kevin; Grandi, Paola; Bantscheff, Marcus; Bergamini, Giovanna

doi:10.1158/2767-9764.27024113.v1

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Figure S5 from Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation

journal contribution

posted on 2024-09-16, 07:20 authored by Anna Rutkowska, H. Christian Eberl, Thilo Werner, Marco L. Hennrich, Daniel C. Sévin, Massimo Petretich, James P. Reddington, Shirin Pocha, Stephan Gade, Amalia Martinez-Segura, Dmytro Dvornikov, Joel Karpiak, Gavain M.A. Sweetman, Christian Fufezan, Birgit Duempelfeld, Florian Braun, Christopher Schofield, Hakan Keles, David Alvarado, Zhuo Wang, Keith H. Jansson, Maria Faelth-Savitski, Edward Curry, Katja Remlinger, Euan A. Stronach, Bin Feng, Geeta Sharma, Kevin Coleman, Paola Grandi, Marcus Bantscheff, Giovanna Bergamini

Co-inhibition of PARP and cholesterol biosynthesis pathway increase efficiency of tumor cell killing

History

ARTICLE ABSTRACT

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 catalyzing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of the cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism. The presented data indicate, to our knowledge, for the first time, the potential benefit of concomitant modulation of cholesterol biosynthesis pathway and PARP inhibition and highlight the need for further investigation to assess its translational relevance.