2. Academic Validation
  3. Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction

Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction

  • Sci Adv. 2022 Sep 16;8(37):eabm9427. doi: 10.1126/sciadv.abm9427.
Kenji M Fujihara 1 2,  Bonnie Z Zhang 1 2,  Thomas D Jackson 3 4,  Moses O Ogunkola 5,  Brunda Nijagal 6,  Julia V Milne 1 2,  David A Sallman 7,  Ching-Seng Ang 4,  Iva Nikolic 8,  Conor J Kearney 2 9,  Simon J Hogg 2 9 10,  Carlos S Cabalag 1 2 11,  Vivien R Sutton 2 12,  Sally Watt 2 12,  Asuka T Fujihara 1,  Joseph A Trapani 2 12,  Kaylene J Simpson 2 8,  Diana Stojanovski 3,  Silke Leimkühler 5,  Sue Haupt 2 13,  Wayne A Phillips 1 2 14 15,  Nicholas J Clemons 1 2
Affiliations

Affiliations

  • 1 Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 2 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
  • 3 Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
  • 4 Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
  • 5 Institute of Biochemistry and Biology Department for Molecular Enzymology, University of Potsdam, Potsdam, Germany.
  • 6 Metabolomics Australia, The Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia.
  • 7 Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • 8 Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 9 Translational Hematology Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 10 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 11 Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 12 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 13 Tumor Suppression and Cancer Sex Disparity Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 14 Department of Surgery (St. Vincent's Hospital), The University of Melbourne, Parkville, Victoria, Australia.
  • 15 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
PMID: 36103522 DOI: 10.1126/sciadv.abm9427
Abstract

The mechanism of action of eprenetapopt (APR-246, PRIMA-1MET) as an Anticancer agent remains unresolved, although the clinical development of eprenetapopt focuses on its reported mechanism of action as a mutant-p53 reactivator. Using unbiased approaches, this study demonstrates that eprenetapopt depletes cellular antioxidant glutathione levels by increasing its turnover, triggering a nonapoptotic, iron-dependent form of cell death known as Ferroptosis. Deficiency in genes responsible for supplying Cancer cells with the substrates for de novo glutathione synthesis (SLC7A11, SHMT2, and MTHFD1L), as well as the enzymes required to synthesize glutathione (GCLC and GCLM), augments the activity of eprenetapopt. Eprenetapopt also inhibits iron-sulfur cluster biogenesis by limiting the cysteine desulfurase activity of NFS1, which potentiates Ferroptosis and may restrict cellular proliferation. The combination of eprenetapopt with dietary serine and glycine restriction synergizes to inhibit esophageal xenograft tumor growth. These findings reframe the canonical view of eprenetapopt from a mutant-p53 reactivator to a Ferroptosis inducer.

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