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Updated: Dec 30, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma
Federica Ganci1, Claudio Pulito1, Sara Valsoni2
1Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Purpose:
Mutation of TP53 gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. TP53 mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC.
Experimental Design:
Mutant p53-associated functions were investigated through gene set enrichment analysis in the Cancer Genome Atlas cohort of HNSCC and in a panel of 22 HNSCC cell lines. Mutant p53-dependent transcripts were analyzed in HNSCC cell line Cal27, carrying mutant p53H193L; FaDu, carrying p53R248L; and Detroit 562, carrying p53R175H. Drugs impinging on mutant p53-MYC-dependent signature were identified interrogating Connectivity Map (https://clue.io) derived from the Library of Integrated Network-based Cellular Signatures (LINCS) database (http://lincs.hms.harvard.edu/) and analyzed in HNSCC cell lines and patient-derived xenografts (PDX) models.
Results:
We identified a signature of transcripts directly controlled by gain-of-function mutant p53 protein and prognostic in HNSCC, which is highly enriched of MYC targets. Specifically, both in PDX and cell lines of HNSCC treated with the PI3Kα-selective inhibitor BYL719 (alpelisib) the downregulation of mutant p53/MYC-dependent signature correlates with response to this compound. Mechanistically, mutant p53 favors the binding of MYC to its target promoters and enhances MYC protein stability. Treatment with BYL719 disrupts the interaction of MYC, mutant p53, and YAP proteins with MYC target promoters. Of note, depletion of MYC, mutant p53, or YAP potentiates the effectiveness of BYL719 treatment.
Conclusions:
Collectively, the blocking of this transcriptional network is an important determinant for the response to BYL719 in HNSCC.
Insights
TP53 gene mutations in head and neck squamous cell carcinoma (HNSCC) drive MYC targets, leading to radioresistance. Targeting this mutant p53-MYC network with BYL719 (alpelisib) shows promise for HNSCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TP53 gene mutations are common in head and neck squamous cell carcinoma (HNSCC) and confer gain-of-function properties.
- Mutant p53 is associated with radioresistance and local recurrence in HNSCC, representing an underexploited therapeutic target.
Purpose of the Study:
- To investigate mutant p53-associated functions and identify therapeutic strategies targeting the mutant p53-MYC network in HNSCC.
- To evaluate the efficacy of drugs targeting the mutant p53-MYC signature in HNSCC models.
Main Methods:
- Gene set enrichment analysis was performed on HNSCC cohorts and cell lines.
- Transcriptional analysis of mutant p53-dependent genes was conducted in HNSCC cell lines with specific TP53 mutations.
- Drug screening was performed using the Connectivity Map (LINCS database) to identify compounds affecting the mutant p53-MYC signature in HNSCC cell lines and patient-derived xenografts (PDX).
Main Results:
- A prognostic transcript signature controlled by gain-of-function mutant p53, enriched for MYC targets, was identified in HNSCC.
- Downregulation of this mutant p53/MYC signature correlated with response to the PI3Kα inhibitor BYL719 (alpelisib) in HNSCC cell lines and PDX models.
- Mechanistically, mutant p53 enhances MYC binding to target promoters and protein stability; BYL719 disrupts these interactions, and MYC, mutant p53, or YAP depletion potentiates BYL719 efficacy.
Conclusions:
- Blocking the mutant p53-MYC-YAP transcriptional network is crucial for HNSCC response to BYL719.
- Targeting this network represents a potential therapeutic strategy for HNSCC patients with TP53 mutations.
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