Targeting the DNA Damage Response in OSCC with TP53 Mutations

Abstract

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the current treatments for OSCC patients. Despite recent advances in these treatment modalities, the overall survival remains poor over the past years. Recent data from whole-exome sequencing reveal that TP53 is commonly mutated in human papillomavirus-negative OSCC patients. Furthermore, these data stressed the importance of the TP53 gene in suppressing the development and progression of OSCC. Clinically, TP53 mutations are largely associated with poor survival and tumor resistance to radiotherapy and chemotherapy in OSCC patients, which makes the TP53 mutation status a potentially useful molecular marker prognostic and predictive of clinical response in these patients. Several forms of DNA damage have been shown to activate p53, including those generated by ionizing radiation and chemotherapy. The DNA damage stabilizes p53 in part via the DNA damage signaling pathway that involves sensor kinases, including ATM and ATR and effector kinases, such as Chk1/2 and Wee1, which leads to posttranscriptional regulation of a variety of genes involved in DNA repair, cell cycle control, apoptosis, and senescence. Here, we discuss the link of TP53 mutations with treatment outcome and survival in OSCC patients. We also provide evidence that small-molecule inhibitors of critical proteins that regulate DNA damage repair and replication stress during the cell cycle progression, as well as other molecules that restore wild-type p53 activity to mutant p53, can be exploited as novel therapeutic approaches for the treatment of OSCC patients bearing p53 mutant tumors.

COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms

“…Several attempts have been made to design molecules that target mutant p53 in cancer cells (27). However, with the exception of PRIMA-1 Met , all p53 reactivators showed unacceptable toxicities in mice precluding further clinical development (27).…”

Bardoxolone-Methyl (CDDO-Me) impairs tumor growth and radioresistance of oral squamous cell carcinoma (OSCC) cells via accumulation of reactive oxygen species

“…The therapeutic window for radiotherapy is mainly narrowed by local side effects mainly due to damage of surrounding normal tissue when targeting cancer sites. Aside from the recent implementation and constant advancement of intensity-modulated radiotherapy (IMRT), a further strategy to restrict radiation doses for neighboring normal cells lies within the identi cation of small-molecule drugs allowing for the radiosensitization of cancer cells and ideally with a radio-protective effect on healthy tissue (3)(4)(5).…”

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

“…Oral squamous cell carcinoma (OSCC) is one of the most common cancers, counting for more than 90% of all histological subtypes of oral cancer [1,2]. About 300,000 new cases are estimated to be diagnosed annually worldwide, and locoregional recurrences may occur in 30-35% of patients, 20% of whom die of OSCC eventually [3,4]. The high recurrence and metastasis rate of OSCC lead to the 5-year survival rate of less than 50% [5,6].…”