Targeting TP53 to augment therapeutic response in head and neck cancer

Despite recent advances in treatment modalities, patient survival for non-viral mediated oropharyngeal cancer patients continues to remain poor over the past years. Whole-exome sequencing studies reveal that TP53 is commonly mutated in human papillomavirus-negative HNSCC patients. Clinically, TP53 mutations are significantly associated with poor survival and tumor resistance to radiotherapy and chemotherapy in HNSCC patients, suggesting a potential utilization of the TP53 mutational status as a useful molecular prognostic marker to predict clinical response. Several approaches for restoration of wild-type p53 function in HNSCC tumors have been developed using gene transfer therapy via adenovirus and nanoparticles delivery. These approaches have shown relative success inducing cell-cycle arrest and apoptosis. Recently, small molecules that specifically reactivate mutant p53 and trigger mutant p53-dependent apoptosis have been developed and tested in clinical trials and show great promise. Targeting HNSCC cells harboring mutant p53 with ATR, Chk1/2 and Wee1 inhibitors alone or in combination with chemotherapy and/or radiation has become an intensive area of investigation. Numerous studies have revealed a novel function of p53 in regulation of cellular metabolism. A compelling evidence for a novel gain-of-function (GOF) of mutant p53 proteins in promoting metabolic changes has been recently demonstrated in HNSCC. We have demonstrated that TP53 mutations are associated with poor clinical outcome and increased radioresistance in HNSCC. We have also provided evidence that metformin acts as a radiosensitizer in vitro in TP53 mutant HNSCC by increasing expression of p21 and reactive oxygen species (ROS) levels, leading to induction of cellular senescence. Collectively, these novel strategies raise hopes for more effective therapies for head and neck cancers.