Mutations in the TP53 gene are a frequent cause of cancer and have become a focus for new treatments. The Y220C mutation, which ranks as the ninth most common TP53 alteration, creates a specific cavity in the protein structure that can be targeted by drugs. Rezatapopt is one such drug designed to restore normal p53 function by binding to this cavity. While early results with rezatapopt have been promising, resistance to the drug can develop over time.
Researchers at Mass General Brigham have published findings in Cancer Discovery identifying new mutations that contribute to resistance against rezatapopt. Their study involved analyzing blood and tumor samples from two patients participating in the ongoing PYNNACLE clinical trial. Both patients initially responded to rezatapopt but later developed resistance.
Genetic testing revealed several new TP53 mutations arising during treatment, including nearly 100 additional mutations found in one patient’s tumor DNA. To understand how these changes led to resistance, researchers introduced the new mutations alongside Y220C into cultured cancer cells.
The study found that the acquired mutations could be divided into two groups: those that affected p53’s transcriptional activity and impaired its function, and those that likely changed the Y220C pocket and prevented rezatapopt from binding effectively.
"The former class of mutation is more likely to cause universal drug resistance to all agents within this therapeutic class, while the latter may be more drug-specific and circumvented with improved strategies, such as next-generation Y220C reactivators with a distinct mode of action," according to the authors. They add that further studies involving larger patient groups will be necessary to better understand different forms of acquired drug resistance.
