Inducers of ferroptosis are potential drugs to target p53-mutated TNBC cells

Expression of a mutant p53-gene sensitises triple-negative breast cancer (TNBC) cells to death by ferroptosis. The experimental drug ML-162 induces ferroptosis in p53-mutated TNBCs and demonstrated anti-cancer activity in vitro and in vivo.

Up to 85% of TNBCs have a p53 mutation as their oncogenic driver. Due to this high frequency of p53 mutations in TNBCs, targeting p53 mutants in a clinical setting could be highly attractive if pathways exist that, when inhibited, will induce the specific death of p53-mutant breast cancer cells, but not p53-wild type breast cells. Dr William Tahaney (MD Anderson Cancer Center, TX, USA) presented first results of the search for these pathways and drugs that can inhibit them [1].

In vitro and in silico drug screens identified 6 potential drugs that inhibit growth of p53-mutant TNBCs but not p53-wild type TNBCs. One drug, the perodixase inhibitor ML-162, was selected for further study and was found to induce death through ferroptosis, and not apoptosis or necroptosis. The effect of ML-162 was demonstrated in vivo by treating p53-mutant TNBC xenografts in nude mice with ML-162. This treatment significantly reduced tumour volume and induced lipid peroxidation, a hallmark of ferroptosis.

“In conclusion, our high-throughput screening demonstrated that several of the identified drugs suppress growth or induce death preferentially in p53-mutant TNBCs. One of these drugs, ML-162, induces death of p53-mutant TNBCs through induction of ferroptosis. Therefore, these studies provide the basic science foundation to further develop ferroptosis inducers for the targeted treatment of p53-mutant breast cancers,” concluded Dr Tahaney.

1. Tahaney WM, et al. Inhibition of GPX4 induces preferential death of p53-mutant triple-negative breast cancer cells. GS1-09, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January 202225 March 2024