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

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.

Administration of 4‑hexylresorcinol increases p53‑mediated transcriptional activity in oral cancer cells with the p53 mutation

“…The transcriptional activity of p53 was significantly increased by 4HR administration in both YD-15 and YD-9 cells. Several chemicals have been identified that can change the conformation of mutant p53 ( 9 ). However, most of these increase the production of ROS ( 9 ).…”

“…The TP53 mutation is a frequent finding in oral cancer ( 7 , 8 ). Several strategies against mutant TP53 have been developed ( 8 , 9 ). The most frequent site of TP53 mutation is the DNA-binding site ( 4 ).…”

“…This strategy can be classified into the following three categories: i) targeting the degradation or direct inhibition of mutant p53; ii) binding to mutant p53 and inducing conformation change to a desirable form; and iii) targeting the viral enzymes that are responsible for the degradation of p53 ( 9 ). In particular, small molecules that can bind to mutant p53, inducing mutant p53 conformational changes, have been a specific focus in recent studies ( 9 ). PRIMA-1, APR-246 and CP-31398 are chemicals that can bind to p53, inducing mutant p53 conformational changes ( 9 ).…”

“…In particular, small molecules that can bind to mutant p53, inducing mutant p53 conformational changes, have been a specific focus in recent studies ( 9 ). PRIMA-1, APR-246 and CP-31398 are chemicals that can bind to p53, inducing mutant p53 conformational changes ( 9 ). Although these chemicals are interesting in terms of restoring mutant p53 conformation, they generate reactive oxygen species (ROS) by suppressing antioxidant enzymes ( 14 ).…”

Inhibiting the Priming for Cancer in Li-Fraumeni Syndrome

“…Of course, re-purposing is not the only option, and there are a number of small molecule drugs being developed to restore wild-type activity in mutant p53 [ 171 ]. A recent review of such strategies in head and neck squamous cell carcinoma, a malignancy with high rates of somatic TP53 mutations, included the agents PRIMA-1, APR-246, RITA, COTI-2 and CP-31398 [ 172 ]. Another interesting avenue of exploration is zinc metallochaperones (ZMCs)—small molecule agents that reactivate zinc-deficient p53 mutants [ 173 ].…”