Targeting Mutant p53 with Arsenic Trioxide

Background: 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 leukemia, 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.Methods: The anti-proliferative effects of ATO were evaluated on a panel of 20 breast cancer cell lines using the MTT assay. Differential gene expression mediated by ATO was assessed by RNA-seq with confirmation by RT-PCR. Pathways altered by ATO were determined by gene ontology analysis.Results: TNBC cell lines were more sensitive to ATO than non-TNBC cell lines (p = 0.0453). Consistent with its ability to reactivate mutant p53, ATO was a more potent inhibitor of proliferation in mutant p53 cell lines than in wildtype p53 cell lines (p = 0.0274). Direct evidence of mutant p53 reactivation was the induction of multiple wild-type p53 canonical target genes such as CDKN1A, SLC7A11, HMOX1, BBC3, PUMA, SESN2, SRXN1 and TXNRD1.Conclusion: Our findings support the activation of mutant p53 by ATO and furthermore, the possible repurposing of ATO to treat TP53 mutated TNBC.