Mutant p53 drives anti-oestrogen therapy resistance in ovarian cancer

Why do hormone-blocking drugs sometimes fail in ovarian cancer? Scientists at The Wistar Institute have uncovered a key reason. Their study [1] shows that mutant p53, a protein altered in 96% of high-grade serous ovarian cancers, disrupts oestrogen signalling, leaving tumours resistant to hormone-blocking therapy and pointing to potential strategies to restore treatment effectiveness.

Importantly, the team found a way to override this resistance using a drug already in clinical trials. By combining the treatment with anti-oestrogen therapy, previously resistant tumours regained sensitivity — offering a potential new lifeline for patients.

“Mutant p53 has been a major roadblock in hormone therapy,” said Maureen Murphy, PhD, Deputy Director of the Ellen and Ronald Caplan Cancer Center and senior author of the study. “Now we know why treatments fail, and we have a strategy to make them work.”

High-grade serous ovarian cancer remains a deadly disease, with an 80% relapse rate after chemotherapy. Although most tumours express oestrogen receptors, anti-oestrogen drugs show limited clinical benefit. Murphy’s team traced the problem to mutant p53 physically binding oestrogen receptors, disrupting crucial hormone signalling.

“This combination therapy could move into clinical trials relatively quickly,” Murphy added. “And the findings may extend beyond ovarian cancer, potentially explaining hormone therapy resistance in other cancers like breast cancer.”

Collaborating with the Helen F. Graham Cancer Center & Research Institute and the University of Pennsylvania, the researchers confirmed that silencing mutant p53 restores drug sensitivity. They also tested rezatapopt, a compound that refolds a specific p53 variant, and found it dramatically boosted response to hormone therapy.

The team is now expanding their work to other p53 variants and developing methods to identify which patients could benefit most from p53-targeted combination treatments. Work supported by: National Institutes of Health (NIH) grants CA102184 and CA266075 (M.E.M.); Department of Defense grant HT94252410206 (N.Z.); V Foundation for Cancer Research grant V2024-026 (N.Z.); and the Elaine M. Ominsky, Ph.D. Breast Cancer Research Endowed Fund (M.E.M.).

More information online

1. Mutant p53 Binds and Controls Estrogen Receptor Activity to Drive Endocrine Resistance in Ovarian Cancer published in Genes and Development, 2025. Online publication.