Publication Date:
2015-05-27
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506213/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506213/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alexandrova, E M -- Yallowitz, A R -- Li, D -- Xu, S -- Schulz, R -- Proia, D A -- Lozano, G -- Dobbelstein, M -- Moll, U M -- 1R01CA176647/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA176647/CA/NCI NIH HHS/ -- T32 HD007505/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):352-6. doi: 10.1038/nature14430. Epub 2015 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA. ; Institute of Molecular Oncology, University of Gottingen, 37077 Gottingen, Germany. ; Synta Pharmaceuticals Corp., Lexington, Massachusetts 02421, USA. ; Department of Cancer Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA [2] Institute of Molecular Oncology, University of Gottingen, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26009011" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Allografts
;
Animals
;
Apoptosis/drug effects
;
Cell Line, Tumor
;
Disease Models, Animal
;
Female
;
HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism
;
Histone Deacetylases/metabolism
;
Humans
;
Lymphoma/*drug therapy/genetics/*metabolism/pathology
;
Male
;
Mice
;
Molecular Targeted Therapy/*methods
;
Mutant Proteins/*antagonists & inhibitors/genetics/metabolism
;
Neoplasm Transplantation
;
*Protein Stability/drug effects
;
Survival Rate
;
Tamoxifen/pharmacology/therapeutic use
;
Triazoles/pharmacology/therapeutic use
;
Tumor Suppressor Protein p53/*antagonists & inhibitors/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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