TY  - JOUR
A1  - Fujihara, Kenji M.
A1  - Zhang, Bonnie Z.
A1  - Jackson, Thomas D.
A1  - Ogunkola, Moses
A1  - Nijagal, Brunda
A1  - Milne, Julia V.
A1  - Sallman, David A.
A1  - Ang, Ching-Seng
A1  - Nikolic, Iva
A1  - Kearney, Conor J.
A1  - Hogg, Simon J.
A1  - Cabalag, Carlos S.
A1  - Sutton, Vivien R.
A1  - Watt, Sally
A1  - Fujihara, Asuka T.
A1  - Trapani, Joseph A.
A1  - Simpson, Kaylene J.
A1  - Stojanovski, Diana
A1  - Leimkühler, Silke
A1  - Haupt, Sue
A1  - Phillips, Wayne A.
A1  - Clemons, Nicholas J.
T1  - Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction
JF  - Science Advances
N2  - The mechanism of action of eprenetapopt (APR-246, PRIMA-1MET) as an anticancer agent remains unresolved, al-though 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 limit-ing 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.
Y1  - 2022
U6  - https://doi.org/10.1126/sciadv.abm9427
SN  - 2375-2548
VL  - 8
IS  - 37
PB  - American Assoc. for the Advancement of Science
CY  - Washington
ER  -