Study Reveals How Mutant p53 Protein Fuels Tumor Growth

Researchers at the Walter and Eliza Hall Institute have unraveled a longstanding mystery surrounding the p53 protein, a critical player in cancer development. Mutations in the p53 protein, found in half of all human cancers, significantly elevate the risk of cancer. The study sheds light on the specific behaviors of the mutated protein crucial for fueling tumor growth, opening new avenues for potential treatment options.

The p53 protein, when functioning correctly, acts as a robust defense mechanism, preventing the formation of cancerous cells by repairing or eliminating those with compromised DNA. Environmental factors and genetic inheritance can trigger mutations, leading to a dysfunctional protein with a loss-of-function, impairing its ability to regulate cellular responses against tumor development.

Contrary to previous beliefs, the study, published in Cancer Discovery, provides evidence that it is the loss-of-function, not gain-of-function, that drives cancer growth in cases of p53 mutations. According to co-corresponding author Gemma Kelly, “Our study has provided the first evidence to show that it is actually the loss-of-function that impacts cancer growth. We found no evidence of gain-of-function contributing to cancer growth.” 

The research, leveraging the CRISPR gene-editing tool, removed 12 different mutated versions of the p53 protein, debunking the notion of gain-of-function effects on cancer cells' behavior or response to chemotherapy. Collaborating with the University of Trento in Italy, the team restored normal functions lost due to mutations, reducing cancer growth in pre-clinical models.

First author Dr Zilu Wang used these models and data from the DepMap database to consolidate the findings. “Having these tools at my disposal allowed me to assess 157 different p53 mutations,” Dr Wang said. “The mutations I looked at basically account for at least 90% of human cancers with defects in p53, which will provide crucial insight when informing the development of new anti-cancer strategies.”