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Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target. | LitMetric

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target.

Cancers (Basel)

Institute of Molecular Oncology, University of Göttingen, 37077 Göttingen, Germany.

Published: June 2018

AI Article Synopsis

  • * Mutated p53 proteins (mutp53) are stabilized in tumors, which aids their aggressive behavior, largely due to protection from E3 ubiquitin ligases through specific chaperone proteins.
  • * Research using mouse models shows that tumors with stabilized mutp53 proteins rely on them for survival, presenting new opportunities for targeted cancer therapies, which are currently being explored in preclinical studies.

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025530PMC
http://dx.doi.org/10.3390/cancers10060188DOI Listing

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