PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer

• DOI: 10.1016/j.redox.2021.101928
• Publication Date: 2021-03-07T17:19:53Z
• Authors: Ting Hong; Guang Lei; Xue Chen; He Li; Xiaoye Zhang; Nayiyuan Wu; Yu Zhao; Yilei Zhang; Jing Wang
• Keywords: Olaparib; PARP inhibitor; Synthetic Lethality

Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most patients carry wild-type BRCA1/2 with no significant clinical benefits from inhibitors, calling needs to further understanding and developing new when employing inhibitors treat Here, we show that ferroptosis, a form regulated cell death driven by iron-dependent phospholipid peroxidation, partly responsible efficacy inhibitor olaparib. Mechanistically, pharmacological or genetic deletion downregulates expression cystine transporter SLC7A11 in p53-dependent manner. Consequently, decreased glutathione biosynthesis caused repression promotes lipid peroxidation ferroptosis. Furthermore, ferroptosis perturbation results resistance olaparib without affecting DNA damage response, while boosting inducers (FINs) synergistically sensitizes BRCA-proficient cancer cells xenografts inhibitor. Together, our reveal previously unappreciated mechanism coupling suggest combination FINs treatment