Mutant p53 in Cancer: Accumulation, Gain-of-Function, and Therapy

Abstract

Tumor suppressor p53 plays a central role in tumor suppression. p53 is the most frequently mutated gene in human cancer, and over half of human cancers contain p53 mutations. Majority of p53 mutations in cancer are missense mutations, leading to the expression of full-length mutant p53 protein. While the critical role of wild type p53 in tumor suppression has been firmly established, mounting evidence has demonstrated that many tumor-associated mutant p53 proteins not only lose tumor suppressive function of wild type p53, but also gain new activities to promote tumorigenesis independently of wild type p53, termed gain-of-function. Mutant p53 protein often accumulates to very high levels in tumors, contributing to malignant progression. Recently, mutant p53 has become an attractive target for cancer therapy. Further understanding of the mechanisms underlying mutant p53 protein accumulation and gain-of-function will accelerate the development of targeted therapies for human cancer harboring mutant p53. In this review, we summarize the recent advances in the studies on mutant p53 protein accumulation and gain-of-function as well as targeted therapies for mutant p53 in human cancer.

Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion

“…Groups 0 and 1 were combined to form ‘p53 low ’, and groups 2 and 3 were combined to form ‘p53 high ’. Missense mutant p53 often accumulates in tumor cells due to pronounced stabilization (Yue et al, 2017). Thus, strong p53 accumulation is considered a surrogate marker for the presence of a p53 missense mutation.…”

Patterns of mutations in TP53 mutated AML

“…Naturally, patients with nonsense mutations or bi-allelic deletions may not be identified, and these “false negatives” would need to be accounted for. Mechanisms of high mutant TP53 expression have not been clearly elucidated in AML, but may include decreased ubiquitination [48] and disruption of normal MDM2 negative feedback mechanisms on TP53 expression [47, 49]. Overexpression likely contributes to or augments dominant-negative effects and gain-of-function phenotypes imposed by the associated missense variants.…”

“…Because TP53 mutated protein consistently leads to protein stabilization and overexpression, there has been an interest to develop therapeutic strategies that are capable of destabilizing accumulated mutant TP53 protein [36, 47, 49]. It is unclear at this time whether these will necessarily be mutation specific, or whether drugs can be developed that will destabilize diverse mutant forms.…”

TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

“…Mutations in TP53 have been identified in the early pathogenesis of high grade serous ovarian cancer, with 96% of these having a TP53 mutation as per the Cancer Genome Atlas 5 6. P53, the protein product of TP53 , mediates the transcription of genes involved in apoptosis and senescence 7. Loss of function of p53 promotes carcinogenesis.…”