Restoring p53 Function in Head and Neck Squamous Cell Carcinoma to Improve Treatments.

Tycho De Bakker,Fabrice Journe,Mohammad Krayem,Sven Saussez,Dirk Van Gestel,Ghanem Ghanem,Géraldine Descamps,Tatiana Dragan

doi:10.3389/fonc.2021.799993

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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in 890.000 patients each year worldwide, ranking it as the sixth most common cancer in the world [1]
Among the viruses being investigated are the herpes simplex virus [63], maraba virus [64] and adenoviral particles. For those types of treatments in this review, we focus on the viral treatments that influence p53 but that is not the only mechanism by which these viral treatments exert antitumoral effects
This review discusses the current status of pharmacological manipulation of p53 for the treatment of head and neck squamous cell carcinoma (HNSCC)

Summary

INTRODUCTION

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in 890.000 patients each year worldwide, ranking it as the sixth most common cancer in the world [1]. P53 is responsible for the transcription activation of many genes involved in cell cycle arrest, apoptosis, senescence, DNA repair and metabolism [6]. In cells with wild-type p53 (WT p53), double- and singlestranded breaks in the DNA activate kinases such as ataxiatelangiectasia mutated (ATM) and ATM and Rad related (ATR), respectively [11], which in turn directly phosphorylate p53 at Ser-15 and will activate checkpoint kinase 2 (CHK2) and checkpoint kinase 1 (CHK1), respectively The latter will subsequently phosphorylate Ser-20 of p53, inducing a change in its conformation and removing inhibition of p53 by mouse double minute 2 (MDM2) which dissociates from p53 [12, 13]. With high-risk HPV, E6 can lead to accumulation of mutations, eventually leading to the activation of oncogenes and the transformation into cancer cells [28]

HNSCC subtype

Triptolide and Minnelide

Findings

CONCLUSION