Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• The p53 pathway is crucial for tumor suppression, with TP53 mutations common in cancer.
• Mutant p53 proteins often gain stability and can inhibit wild-type p53 function via a dominant-negative mechanism.
• Understanding how mutant p53 inactivates wild-type p53 is key for developing targeted therapies.

Purpose of the Study:

• To elucidate the precise mechanism by which mutant p53 interferes with wild-type p53 activity.
• To evaluate the therapeutic potential of selectively degrading mutant p53 in cancer models.

Main Methods:

• Investigated the dominant-negative effect of p53R248Q mutant on wild-type p53.
• Utilized degron-tagged constructs and molecular glues (e.g., iberdomide) to selectively degrade mutant p53.
• Combined mutant p53 degradation with MDM2 inhibition in experimental models.

Main Results:

• Established that mutant p53's longer half-life creates an imbalance, favoring the dominant-negative inhibition of wild-type p53.
• Demonstrated that exogenous wild-type p53 or selective mutant p53 degradation can overcome this inhibition.
• Observed significant therapeutic efficacy when combining mutant p53 degradation with MDM2 inhibition.

Conclusions:

• Mutant p53 inactivates wild-type p53 through a dose-dependent dominant-negative mechanism.
• Selective degradation of mutant p53, particularly in combination with MDM2 inhibitors, represents a promising therapeutic strategy for cancers retaining a wild-type TP53 allele.