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

• Published in: Science advances Vol. 8; no. 37; p. eabm9427
• Main Authors: Fujihara, Kenji M., Zhang, Bonnie Z., Jackson, Thomas D., Ogunkola, Moses O., Nijagal, Brunda, Milne, Julia V., Sallman, David A., Ang, Ching-Seng, Nikolic, Iva, Kearney, Conor J., Hogg, Simon J., Cabalag, Carlos S., Sutton, Vivien R., Watt, Sally, Fujihara, Asuka T., Trapani, Joseph A., Simpson, Kaylene J., Stojanovski, Diana, Leimkühler, Silke, Haupt, Sue, Phillips, Wayne A., Clemons, Nicholas J.
• Format: Journal Article
• Language: English
• Published: American Association for the Advancement of Science 16.09.2022
• Subjects: Biomedicine and Life Sciences; Cancer; Immunology; Life Sciences; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abm9427

The mechanism of action of eprenetapopt (APR-246, PRIMA-1 MET ) 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. The mutant-p53 reactivator, eprenetapopt, kills tumor cells through inducing ferroptosis and not apoptosis.