2. Academic Validation
  3. Synergistic effects of PARP inhibition and cholesterol biosynthesis pathway modulation

Synergistic effects of PARP inhibition and cholesterol biosynthesis pathway modulation

  • Cancer Res Commun. 2024 Jul 19. doi: 10.1158/2767-9764.CRC-23-0549.
Anna Rutkowska 1,  H Christian Eberl 1,  Thilo Werner 1,  Marco L Hennrich 1,  Daniel C Sévin 1,  Massimo Petretich 1,  James P Reddington 1,  Shirin Pocha 1,  Stephan Gade 1,  Amalia Martinez-Segura 2,  Dmytro Dvornikov 1,  Joel Karpiak 3,  Gavain M A Sweetman 1,  Christian Fufezan 4,  Birgit Duempelfeld 1,  Florian Braun 5,  Christopher Schofield 6,  Hakan Keles 6,  David Alvarado 3,  Zhuo Wang 7,  Keith H Jansson 8,  Maria Faelth-Savitski 1,  Edward Curry 9,  Katja Remlinger 3,  Euan A Stronach 10,  Bin Feng 11,  Geeta Sharma 3,  Kevin Coleman 3,  Paola Grandi 1,  Marcus Bantscheff 1,  Giovanna Bergamini 1
Affiliations

Affiliations

  • 1 Cellzome, a GSK company, Heidelberg, Germany.
  • 2 T-Cypher Bio, United Kingdom.
  • 3 GlaxoSmithKline, United States.
  • 4 GSK Heidelberg, Heidelberg, Germany.
  • 5 European Molecular Biology Laboratory, Germany.
  • 6 GlaxoSmithKline, Stevenage, United Kingdom.
  • 7 GlaxoSmithKline, Cambridge, MA, United States.
  • 8 National Cancer Institute, Bethesda, MD, United States.
  • 9 GlaxoSmithKline, United Kingdom.
  • 10 Imperial College London, London, United Kingdom.
  • 11 GlaxoSmithKline (United States), Waltham, United States.
PMID: 39028932 DOI: 10.1158/2767-9764.CRC-23-0549
Abstract

An in-depth multi-omic molecular characterisation of poly(adenosine 5'-diphosphate [ADP]-ribose) polymerase (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 signalling branch of the Cholesterol biosynthesis pathway. Interestingly, the combination of a LSS inhibitor with a PARP Inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing of Cancer cells to levels comparable to Niraparib as single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of HMGCR, an Enzyme catalysing 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 Cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on Cholesterol metabolism.

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