Faculty, Staff and Student Publications
Language
English
Publication Date
1-6-2026
Journal
Breast Cancer Research and Treatment
DOI
10.1007/s10549-025-07865-6
PMID
41493644
PMCID
PMC12774971
PubMedCentral® Posted Date
1-6-2026
PubMedCentral® Full Text Version
Post-print
Abstract
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 ferroptosis inducer ML-162 was tested both in vitro and in vivo and the mechanism of cell death following ML-162 treatment or GPX4 knockout was determined.
Results: High-throughput drug screening demonstrated that TP53-mutant TNBCs are highly sensitive to peroxidase, cell cycle, cell division, and proteasome inhibitors. We further characterized the effect of the ferroptosis inducer ML-162 and demonstrated that ML-162 induces preferential ferroptosis in TP53-mutant TNBC cells. Treatment of TP53-mutant xenografts with ML-162 suppressed tumor growth and increased lipid peroxidation in vivo. Testing ferroptosis inducers demonstrated TP53-missense mutant, and not TP53-null or wild-type cells, were more sensitive to ferroptosis, and expression of mutant TP53 genes in p53-null cells sensitized cells to ML-162 treatment.
Conclusions: This study demonstrates that TP53-mutant TNBC cells have unique survival pathways that can be effectively targeted. Our results illustrate the intrinsic vulnerability of TP53-mutant TNBCs to ferroptosis and highlight GPX4 as a potential target for the precision treatment of TP53-mutant TNBC.
Keywords
Humans, Triple Negative Breast Neoplasms, Phospholipid Hydroperoxide Glutathione Peroxidase, Female, Tumor Suppressor Protein p53, Animals, Cell Line, Tumor, Mice, Ferroptosis, Xenograft Model Antitumor Assays, Mutation, Antineoplastic Agents, Disease Models, Animal, TNBC, p53, TP53, GPX4, Ferroptosis, Gain-of-function
Published Open-Access
yes
Recommended Citation
Tahaney, William M; Lanier, Amanda; Qian, Jing; et al., "Inhibition of GPX4 Induces the Death of p53-Mutant Triple-Negative Breast Cancer Cells" (2026). Faculty, Staff and Student Publications. 5389.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5389
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons