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Updated: Oct 5, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments
Tycho de Bakker1,2, Fabrice Journe2,3, Géraldine Descamps3
1Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Abstract:
TP53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes p53 an attractive target to improve HNSCC therapy by restoring the tumor suppressor activity of this protein. Therapeutic strategies targeting p53 in HNSCC can be divided into three categories related to three subtypes encompassing WT p53, mutated p53 and HPV-positive HNSCC. First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV+ cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.
Insights
Targeting p53 protein, a common alteration in head and neck squamous cell carcinoma (HNSCC), offers new therapeutic avenues. Strategies focus on wild-type p53, mutated p53, and HPV-positive HNSCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TP53 mutations are frequent in head and neck squamous cell carcinoma (HNSCC), leading to p53 protein accumulation.
- Restoring p53's tumor suppressor function is a key therapeutic goal for HNSCC.
Purpose of the Study:
- To review and classify therapeutic strategies targeting p53 in HNSCC based on p53 mutation status and HPV infection.
- To discuss the combination of p53-targeting therapies with existing HNSCC treatments.
Main Methods:
- Classification of HNSCC based on p53 status (wild-type, mutated, HPV-positive).
- Review of therapeutic compounds targeting p53 pathways, including MDM2/MDMX inhibitors, proteasome inhibitors, mutated p53 reactivators, and HPV E6/E7 targeting agents.
- Discussion of combination strategies for HNSCC treatment.
Main Results:
- Therapeutic strategies are categorized into three main approaches based on HNSCC subtypes.
- Compounds like PM2, RITA, nutlin-3, APR-246, and bortezomib are discussed for their roles in p53 reactivation or targeting.
- A novel classification framework for HNSCC is proposed.
Conclusions:
- Targeting p53 offers promising therapeutic strategies for HNSCC, adaptable to different tumor subtypes.
- Combination therapies hold potential for enhanced treatment efficacy in HNSCC.
- Further research into p53-targeting agents and combination strategies is warranted for HNSCC treatment.
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