Inhibition of GPX4 Induces the Death of p53-Mutant Triple-Negative Breast Cancer
Institutional Repository Document
Overview
Research
Identity
Other
View All
Overview
abstract
AbstractBackground Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, characterized high rates of tumor protein 53 (p53) mutation and limited targeted therapies. Despite being clinically advantageous, direct targeting of mutant p53 has been largely ineffective. Therefore, we hypothesized that there exist pathways upon which p53-mutant TNBC cells rely upon for survival. Methods In vitro and in silico drug screens were used to identify drugs that induced preferential death in p53-mutant breast cancer cells. The effects of the glutathione peroxidase 4 (GPX4) inhibitor ML-162 was deleniated using growth and death assays, both in vitro and in vivo. The mechanism of ML-162 induced death was determined using small molecule inhibition and genetic knockout. Results High-throughput drug screening demonstrated that p53-mutant TNBCs are highly sensitive to peroxidase, cell cycle, cell division, and proteasome inhibitors. We further characterized the effect of the Glutathione Peroxidase 4 (GPX4) inhibitor ML-162 and demonstrated that ML-162 induces preferential ferroptosis in p53-mutant, as compared to p53-wild type, TNBC cell lines. Treatment of p53-mutant xenografts with ML-162 suppressed tumor growth and increased lipid peroxidation in vivo. Testing multiple ferroptosis inducers demonstrated p53-missense mutant, and not p53-null or wild type cells, were more sensitive to ferroptosis, and that expression of mutant TP53 genes in p53-null cells sensitized cells to ML-162 treatment. Finally, we demonstrated that p53-mutation correlates with ALOX15 expression, which rescues ML-162 induced ferroptosis. Conclusions This study demonstrates that p53-mutant TNBC cells have critical, unique survival pathways that can be effectively targeted. Our results illustrate the intrinsic vulnerability of p53-mutant TNBCs to ferroptosis, and highlight GPX4 as a promising target for the precision treatment of p53-mutant triple-negative breast cancer.
