Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?

Simple Summary Cancer is largely caused by genetic alterations such as mutations in a group of genes known as cancer driver genes. Many of the key advances in cancer treatment in recent years have involved blocking these driver genes using a new generation of anti-cancer drugs. Although p53 is the most frequently mutated gene in human cancers, historically, it has proved difficult to develop drugs against it. However, recently, several new drugs have become available for neutralizing the cancer-promoting effects of mutant p53. The aim of this article is to discuss the most promising of these drugs, especially those that are being investigated in clinical trials. Mutant p53 is one of the most attractive targets for new anti-cancer drugs. Although traditionally regarded as difficult to drug, several new strategies have recently become available for targeting the mutant protein. One of the most promising of these involves the use of low molecular weight compounds that promote refolding and reactivation of mutant p53 to its wild-type form. Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. Of these, the most clinically advanced for targeting mutant p53 is eprenetapopt which has completed phase I, II and III clinical trials, the latter in patients with mutant TP53 myelodysplastic syndrome. Although no data on clinical efficacy are currently available for eprenetapopt, preliminary results suggest that the drug is relatively well tolerated. Other strategies for targeting mutant p53 that have progressed to clinical trials involve the use of drugs promoting degradation of the mutant protein and exploiting the mutant protein for the development of anti-cancer vaccines. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.

Automated summary

Cancer is mainly caused by genetic alterations, and targeting mutant p53 with new anti-cancer drugs has become an important research direction for cancer treatment. Several new drugs have been developed to neutralize the cancer-promoting effects of mutant p53, with the most promising strategy involving the use of low molecular weight compounds to restore mutant p53 to its wild-type form. Other strategies being explored include promoting degradation of the mutant protein and developing anti-cancer vaccines. Ongoing clinical trials will determine the effectiveness of targeting mutant p53 for cancer treatment.