TP53 in bone and soft tissue sarcomas.

Document Type

Article

Publication Date

10-2019

Identifier

DOI: 10.1016/j.pharmthera.2019.06.010; PMCID: PMC6746598 (available on 2020-10-01)

Abstract

Genomic and functional study of existing and emerging sarcoma targets, such as fusion proteins, chromosomal aberrations, reduced tumor suppressor activity, and oncogenic drivers, is broadening our understanding of sarcomagenesis. Among these mechanisms, the tumor suppressor p53 (TP53) plays significant roles in the suppression of bone and soft tissue sarcoma progression. Although mutations in TP53 were thought to be relatively low in sarcomas, modern techniques including whole-genome sequencing have recently illuminated unappreciated alterations in TP53 in osteosarcoma. In addition, oncogenic gain-of-function activities of missense mutant p53 (mutp53) have been reported in sarcomas. Moreover, new targeting strategies for TP53 have been discovered: restoration of wild-type p53 (wtp53) activity through inhibition of TP53 negative regulators, reactivation of the wtp53 activity from mutp53, depletion of mutp53, and targeting of vulnerabilities in cells with TP53 deletions or mutations. These discoveries enable development of novel therapeutic strategies for therapy-resistant sarcomas. We have outlined nine bone and soft tissue sarcomas for which TP53 plays a crucial tumor suppressive role. These include osteosarcoma, Ewing sarcoma, chondrosarcoma, rhabdomyosarcoma (RMS), leiomyosarcoma (LMS), synovial sarcoma, liposarcoma (LPS), angiosarcoma, and undifferentiated pleomorphic sarcoma (UPS).

Journal Title

Pharmacology & therapeutics

Volume

202

First Page

149

Last Page

164

MeSH Keywords

Animals; Bone Neoplasms; Humans; Mutation; Osteosarcoma; Sarcoma; Soft Tissue Neoplasms; Tumor Suppressor Protein p53

Keywords

MDM2; TP53; bone; mutation; sarcoma; targeted therap

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