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Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs
Ananthan Sadagopan1,2,3, Maximilian Carson2, Eriks J Zamurs2
1Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Abstract:
TP53 mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in TP53 result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill TP53 mutant cells. This approach uses the increased abundance of p53 protein in TP53 mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53Y220C mutations. The resulting bifunctional molecule promotes formation of a p53Y220C-PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis in TP53Y220C cells while sparing wild-type TP53 cells. These data exemplify a potentially generalizable framework for targeting TP53 missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53's transcriptional activity.
Insights
Scientists developed a new method to target cancer cells with TP53 mutations. This approach concentrates toxic molecules in cancer cells, leading to selective cell death in TP53 mutant cancers while sparing healthy cells.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- TP53 mutations are implicated in approximately 50% of cancer deaths.
- Missense mutations are the most frequent TP53 inactivation mechanism, leading to increased p53 protein levels.
Purpose of the Study:
- To develop an induced proximity strategy for selectively eliminating cancer cells with TP53 mutations.
- To leverage the elevated p53 protein abundance in mutant cells to concentrate cytotoxic agents.
Main Methods:
- Designed a bifunctional molecule targeting the Y220C mutant p53.
- The molecule concentrates a PLK1 inhibitor in cells with TP53 Y220C mutations.
- Investigated the formation of a p53-PLK1 ternary complex and its downstream effects.
Main Results:
- The bifunctional molecule selectively induced G2/M arrest and apoptosis in TP53 Y220C mutant cells.
- Wild-type TP53 cells remained unaffected, demonstrating target specificity.
- Demonstrated successful mislocalization and inhibition of PLK1 activity.
Conclusions:
- This induced proximity approach offers a generalizable framework for targeting TP53 missense mutations.
- The strategy utilizes mutant p53 protein abundance to induce cancer cell death, independent of p53 transcriptional activity.
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