Abstract P1-19-02: Repurposing the FOXO4 senolytic against triple-negative breast cancer

Abstract Metastatic breast cancer is the second most common cause of cancer-related death in women. Triple Negative Breast Cancer (TNBC) has tan especially poor prognosis partly due to these tumors lacking relevant molecular targets. The most commonly mutated gene in TNBC is the tumor suppressor TP53. Mostly, p53 mutations give rise to stably expressed proteins with tumor promoting functions. Therefore, there is an urgent need for therapeutics that can target p53-mutated TNBCs. Here we show that an anti-senescence compound can target metastatic cancers. We found that, in TNBCs, mutant p53 attained a distinctive conformation that has novel oncogenic roles through binding to the transcription factor Forkhead box O (FOXO) 4 sequestered within promyelocytic leukemia (PML) foci. Since these nuclear structures are specific to senescent cells, we tested the senolytic FOXO4 peptide. In cytotoxicity experiments, we found this compound to target TNBCs specifically over other breast cancer subtypes. Most importantly, these compounds decrease metastatic burden in the most commonly-used mouse model for human breast cancer metastasis. In summary, our results demonstrate that mutant p53-driven cancers presented senescent cell-specific characteristics that makes them a great candidate for the FOXO4-directed anti-senescence therapy. We expect that creative repurposing of senolytics to translate to other types of cancer that are driven by mutant p53. Citation Format: Diana Putavet, Marjolein Baar, Tao Shi, Johannes Lehmann, Tim Leyten, Esmee Bouma, Antoine Khalil, Harm-Jan Vos, Boudewijn Burgering, Tobias Dansen, Patrick Derksen, Peter de Keizer. Repurposing the FOXO4 senolytic against triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-19-02.