The tumour suppressor protein p53 protects the body from cancer and is the most frequently mutated gene in human cancer. While many researchers have looked for drugs that can reactivate mutated p53 and therefore treat cancer, this is challenging because of the large variety of p53 mutations and their effects, and the lack of easy sites on the p53 protein to target with drugs. However, over half of all p53 mutations cause structural alterations that affect p53 activity, which represents a different avenue for investigation.
In this paper published in Cancer Cell, Ludwig Oxford’s Dr Shuo Chen from Professor Xin Lu’s lab collaborated with Dr Min Lu’s group (Shanghai Institute of Hematology, Shanghai Jiao Tong University School of Medicine, China) to screen for drugs that could reactivate this class of structural p53 mutants. They found that arsenic compounds – including arsenic trioxide which is FDA-approved to treat acute promyelocytic leukaemia – were able to rescue some of the structural defects in p53 associated with these mutations. Promisingly, for some of the structural p53 mutations, arsenic trioxide was also able to reactivate the tumour suppressor function of p53 in experimental models.
Arsenic trioxide is now being tested in a phase I clinical trial in patients with p53-mutated blood cancers. For future utility in the clinic, the efficiency of arsenic trioxide to reactivate each of the hundreds of different p53 mutants will need to be established to enable a personalised medicine approach to treat p53-mutated cancers.