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Cancer Cell. 2018 Aug 13;34(2):298-314.e7. doi: 10.1016/j.ccell.2018.07.004.

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

Author information

1
Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen 37077, Germany.
2
Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
3
Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen 37075, Germany.
4
Department of Pathology, University Medical Center Göttingen, Göttingen 37075, Germany.
5
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfu am Main 60596, Germany.
6
Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen 37077, Germany. Electronic address: mdobbel@uni-goettingen.de.
7
Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen 37077, Germany; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: ute.moll@stonybrook.edu.

Abstract

Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.

KEYWORDS:

CRC; GOF; Hsp90; Stat3; azoxymethane (AOM)/dextrane sodium sulfate (DSS)-induced CRC model; cancer cell invasion; colorectal cancer; gain-of-function; genetic APC intestinal cancer model; heat shock protein 90; mutant p53; mutp53; signal transducer and activator of transcription 3

PMID:
30107178
PMCID:
PMC6582949
DOI:
10.1016/j.ccell.2018.07.004
[Indexed for MEDLINE]
Free PMC Article

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