The Enigmatic Tumor Suppressor p53 Biomolecule: Its Role and Prognostic and Predictive Values in Cancer Therapy and Precision Medicine

The p53 biomolecule is critical for facile antitumor response in cancer therapy. Once fully activated, p53 will kill tumor cells by activating programmed cell death (PCD), such as apoptosis and ferroptosis, and inducing immunogenic cell death. It is not surprising, therefore, that in about 50% of cancers p53 is mutated and non-functional, which induces drug resistance. Paradoxically, many cancers harboring the wild-type p53 genotype also become resistant via loss of drug-induced activation of p53. Efforts to convert loss-of-function or gain-of-function mutant p53 to the wild-type phenotype or to activate wild-type p53 through drug design have been disappointing. There is also a failure to recognize the existence of a sizeable number of mutant p53s that are phenotypically normal but cannot be functionally activated. Since such mutants and wild-type p53 retain intrinsic PCD pathways, focus on activating p53 could be more rewarding if the efforts implemented recognize and incorporate mechanistic factors that are vital for activating p53 function. This would realize a seminal goal of harnessing the true potential of p53 through more rational and effective therapeutic strategies and finally fulfill a critical unmet clinical need, particularly in the context of precision medicine. For such a vision, functional evaluation of normal (wild-type) or mutant p53 (or FENOMP) is vital and, thus, proposed herein as a conceptual assay to predict the phenotype of p53.