Abstract
p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels.
Highlights
The tumor suppressor TP53 is the single most frequently mutated gene in over 50% of all human cancer patients
Mouse models and clinical data from germline and sporadic cancers have firmly established that p53 missense mutations abolish the tumor suppressive function, and often acquire new tumorigenic driver activities [2,3,4,5]
Given the remarkably high frequency of TP53 missense mutations across all cancer types, this therapeutic concept appears to be broadly applicable for patients worldwide
Summary
The tumor suppressor TP53 is the single most frequently mutated gene in over 50% of all human cancer patients. We recently showed that acute genetic ablation or pharmacologic degradation of mutp in autochthonous tumors triggers strong cytotoxicity in different hotspot GOF knockin mice, translating to suppression of tumorigenesis and major gains in animal survival by up to 59% [15] This antineoplastic effect of mutp removal operates in the absence of wild-type p53 (wtp). Given the remarkably high frequency of TP53 missense mutations across all cancer types, this therapeutic concept appears to be broadly applicable for patients worldwide Another function of mutp, widely observed in ectopic mutp overexpression cell culture models, is the so-called dominant-negative (DN) effect of mutp over all family members, i.e., wild-type p53, TAp63 and TAp73, to inhibit their tumor suppressive functions. It further suggests that ectopic in vitro models might be at least in some cases an artifact of severe overexpression not mimicking the endogenous condition
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