The drug arsenic trioxide can restore the structure and function of some p53 tumor suppressor mutants, with potential as a future personalised cancer treatment strategy.
The tumor suppressor protein p53, often called the “guardian of the genome,” 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 sites on the p53 protein that can be easily targeted with drugs. However, over half of all p53 mutations cause structural alterations that affect p53 activity, which may represent a different opportunity for drug design.
In this paper published in Cancer Cell, Ludwig Oxford’s Shuo Chen in Professor Xin Lu’s lab collaborated with Min Lu’s group at the Shanghai Institute of Hematology in China to screen for drugs that could reactivate this class of structural p53 mutants. They found that arsenic compounds—including arsenic trioxide, approved by the U.S. FDA to treat acute promyelocytic leukemia—were able to rescue some of the structural defects in p53 associated with these mutations. For some of the structural p53 mutations, arsenic trioxide was also able to reactivate the tumor 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 personalized medicine approach to treat p53-mutated cancers.