A study conducted by Mass General Brigham investigators has identified specific mutations in the tumor suppressor protein TP53 that lead to acquired resistance against the cancer drug rezatapopt. The research, published in Cancer Discovery, details how these secondary mutations impair p53 function or disrupt drug binding, providing a molecular basis for therapeutic failure and suggesting potential strategies for overcoming resistance.
Background on TP53 and Rezatapopt
The TP53 gene, which encodes the tumor suppressor protein p53, is frequently mutated in various cancers. The Y220C mutation, noted as the ninth most common TP53 mutation, creates a specific cavity in the mutant protein. Small molecules, such as rezatapopt, have been developed to target this Y220C cavity with the aim of restoring p53's normal tumor suppressor function. While rezatapopt has indicated initial efficacy in early trials, patients have subsequently developed resistance to the treatment.
Study Methodology and Findings
Investigators analyzed blood and tumor samples from two patients participating in the PYNNACLE clinical trial, which evaluates rezatapopt in individuals with metastatic solid tumors carrying a Y220C mutation. Both patients, who had different types of solid tumors, initially responded to rezatapopt treatment but later developed drug resistance.
Genetic analyses of tumor DNA from these patients revealed the emergence of numerous new TP53 mutations during treatment. In one patient's sample, nearly 100 new mutations were observed. To understand the mechanism by which these acquired mutations caused drug insensitivity, the research team expressed the mutations alongside Y220C in cultured cancer cells.
The acquired mutations were categorized into two primary types:
- Impaired Transcriptional Activity: Mutations that altered p53 transcriptional activity, thereby impairing its overall function.
- Disrupted Drug Binding: Mutations that potentially modified the Y220C pocket, disrupting rezatapopt's ability to bind to its target.
Implications for Treatment Resistance
Ferran Fece de la Cruz, PhD, an instructor at the Krantz Family Center for Cancer Research at the Mass General Brigham Cancer Institute, stated that the findings establish a molecular basis for therapeutic failure in rezatapopt-treated patients. The study provides clinical evidence that on-target secondary TP53 mutations can lead to acquired resistance.
The researchers suggest that mutations impairing p53 transcriptional activity are likely to cause universal drug resistance to all agents within this therapeutic class. In contrast, mutations that alter the Y220C pocket may be more drug-specific and could potentially be addressed with alternative strategies, such as next-generation Y220C reactivators that employ a distinct mode of action.
The study encourages further investigation into next-generation agents or combination therapies to delay or overcome the emergence of resistance. Further studies involving larger patient cohorts are considered necessary to fully evaluate various forms of acquired drug resistance.