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Targeting mutant p53 with arsenic trioxide: A preclinical study focusing on triple negative breast cancer
Subhasree Rajaram1, Naoise C Synnott1, John Crown2
1UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin D04 V1W8, Ireland.
Abstract:
New treatments are urgently required for triple-negative breast cancer (TNBC). As TP53 is mutated in approximately 80% of TNBC, it is theoretically an attractive target for new drugs for this disease. Arsenic trioxide (ATO), which is used to treat promyelocytic leukaemia, was recently shown to reactivate mutant p53 and restore wild-type functionality. The aim of this study was to evaluate ATO as a potential new treatment for TNBC. Using a panel of 20 cell lines, we found that TNBC cell lines were more sensitive to ATO than non-TNBC cell lines (P = 0.045). Consistent with its ability to reactivate mutant p53, ATO was a more potent inhibitor of proliferation in cell lines with mutant TP53 than the wildtype TP53 (P = 0.027). Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, BBC3, PMAIP1, SESN2, SRXN1 and TXNRD1. Our findings support the activation of mutant p53 by ATO and, furthermore, the possible repurposing of ATO to treat TP53-mutated TNBC.
Insights
Arsenic trioxide (ATO) shows promise for treating triple-negative breast cancer (TNBC). This study found ATO effectively reactivates mutant p53 in TNBC cells, inhibiting their growth.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) lacks effective targeted therapies.
- TP53 mutations are prevalent in TNBC, presenting a therapeutic target.
- Arsenic trioxide (ATO) can reactivate mutant p53.
Purpose of the Study:
- To evaluate arsenic trioxide (ATO) as a novel treatment for triple-negative breast cancer (TNBC).
- To investigate ATO's efficacy in TNBC cell lines with TP53 mutations.
Main Methods:
- Screening of 20 breast cancer cell lines for sensitivity to ATO.
- Assessing proliferation inhibition in cell lines with wild-type versus mutant TP53.
- Analyzing the induction of p53 target genes as evidence of reactivation.
Main Results:
- TNBC cell lines demonstrated higher sensitivity to ATO compared to non-TNBC lines.
- ATO more potently inhibited proliferation in cell lines with mutant TP53.
- ATO treatment induced canonical wild-type p53 target genes, confirming p53 reactivation.
Conclusions:
- Arsenic trioxide (ATO) effectively reactivates mutant p53 in TNBC.
- ATO shows potential as a repurposed drug for treating TP53-mutated TNBC.
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