Inhibition of GPX4 Induces the Death of p53-Mutant Triple-Negative Breast Cancer Cells

Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high rates of tumor protein 53 (TP53) mutation and with limited targeted therapies. Despite being clinically advantageous, direct targeting of mutant TP53 has been challenging. Therefore, we hypothesized that p53 -mutant TNBC cells rely upon other potentially targetable survival pathways. Methods In vitro and in silico screens were used to identify drugs that induced preferential death in TP53-mutant cells. The effect of the glutathione peroxidase 4 (GPX4) inhibitor ML-162 was tested both in vitro and in vivo and the mechanism of cell death following GPX4 inhibition or knockout was determined. 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 TNBC cells. Treatment of p53 -mutant xenografts with ML-162 suppressed tumor growth and increased lipid peroxidation in vivo . Testing ferroptosis inducers demonstrated p53 -missense mutant, and not p53 -null or wild-type cells, were more sensitive to ferroptosis, and expression of mutant p53 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 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 TNBC.