Format

Send to

Choose Destination
Nature. 2015 Jul 16;523(7560):352-6. doi: 10.1038/nature14430. Epub 2015 May 25.

Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.

Author information

1
Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
2
Institute of Molecular Oncology, University of Göttingen, 37077 Göttingen, Germany.
3
Synta Pharmaceuticals Corp., Lexington, Massachusetts 02421, USA.
4
Department of Cancer Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
5
1] Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA [2] Institute of Molecular Oncology, University of Göttingen, 37077 Göttingen, Germany.

Abstract

Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities. Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization. We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele) and H/H (R172H allele) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.

PMID:
26009011
PMCID:
PMC4506213
DOI:
10.1038/nature14430
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center