Abstract 5212: The benefits of Didox in triple negative breast cancer treatment targeting mutant p53

Triple-negative breast cancer (TNBC) is an aggressive histological subtype of malignancy with limited treatment options. Frequently, doxorubicin (DOXO)- based chemotherapy is utilized in this patient population due to the lack of molecular targets available. While DOXO is an effective chemotherapeutic agent, its efficacy is limited due to acquired drug resistance and cardiotoxicity. Therefore the identification of other treatment options for TNBC is needed. TNBC is a heterogeneous malignancy, with 70% of cases classified as a basal subtype, which further complicates the search for an effective molecular target. However, it has been identified that 80% of TNBC samples carry TP53 (tumor protein p53) mutations, which leads to a mutant p53 protein no longer able to act as a tumor suppressor and thus failing to halt cell growth. Mutant p53, when present in malignant cells, is far less susceptible to degradation than its wild-type counterpart, and thus accumulates within the cell. As such, the TP53 is an attractive therapeutic target for TNBC. We have previously identified that ribonucleotide reductase M2 (RRM2) is upregulated in TNBC cells and is a key contributor to acquired drug resistance. The ribonucleotide reductase inhibitor Didox has been shown to be a powerful free radical scavenger and iron chelator. Through these mechanisms, Didox alleviates the non-selective cytotoxic effects of DOXO on non-cancerous tissue, including cardiotoxicity and potentiates DOXO9s efficacy against malignant cells. We have previously reported that Didox in combination with DOXO effectively treats TNBC by enhancing tumor inhibition and minimizing DOXO-induced heart damage. Our current study shows that Didox alone or in combination with DOXO downregulates mutant p53 protein levels in the mutant p53 TNBC cell lines MDA-MB 468, MDA-MB 231 and BT-20. This effect is notably absent in breast cancer cell lines with wild-type p53, including MCF7, A3B5 and ZR751, where p53 successfully acts as a tumor suppressor allowing for cell cycle arrest or apoptosis after DNA damage. We hypothesize that mutant p53 is a valid therapeutic target in TNBC. As shown here, the addition of Didox downregulates mutant p53 levels and thus enhances tumor inhibition while alleviating DOXO-associated cardiotoxicity. Citation Format: Nahid Sultana, Elizabeth A. Wilson, Khyati N. Shah, Howard L. Elford, Jesika S. Faridi. The benefits of Didox in triple negative breast cancer treatment targeting mutant p53 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5212.