Editors' ChoiceCancer

Drugging mutant p53

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Science Signaling  16 Feb 2021:
Vol. 14, Issue 670, eabh0347
DOI: 10.1126/scisignal.abh0347

Arsenic trioxide may be effective against tumors with structural p53 mutations.

Mutations in the protein p53 are frequent in cancer and drive tumor growth; however, finding drugs that can selectively target and restore normal function to various p53 mutants has been challenging. Chen et al. may have found one that has long been used to target a different protein to treat a form of leukemia. Starting with a drug screen and crystal structure analysis, the authors discovered that arsenic trioxide (ATO) inhibited the proliferation of tumor cell lines that had structural mutations in p53 (mutations that destabilize the folding of its DNA binding domain, or DBD) by covalently binding to multiple cysteines at an allosteric site. ATO binding restored stability to the DBD and consequently restored wild-type transcriptional function to the mutant proteins. These effects were confirmed in cell line– and patient-derived xenografts of various tumor types in mice, suggesting that ATO might be repurposed to additionally treat tumors with structural p53 mutations.

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