Targeting mutant p53 with arsenic trioxide: A preclinical study focusing on triple negative breast cancer

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.

Keywords

• Mutant p53
• ATO
• Triple-negative breast cancer
• Therapy
• RNA-seq
• APR-246