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

• Main Authors: Ramona Schulz-Heddergott, Ute M. Moll
• Format: Article
• Language: English
• Published: MDPI AG 2018-06-01
• Series: Cancers
• Subjects: mutant p53 (mutp53); missense p53; gain-of-function (GOF); p53 loss-of-heterozygosity (LOH); drug therapy; HSP90; HSF1
• Online Access: http://www.mdpi.com/2072-6694/10/6/188

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.