title: Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.
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.
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Alexandrova
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Yallowitz
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: Institute of Molecular Oncology, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schulz
authors.affiliation: Synta Pharmaceuticals Corp., Lexington, Massachusetts 02421, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: Department of Cancer Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lozano
authors.affiliation: Institute of Molecular Oncology, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dobbelstein
authors.affiliation: 1] Department of Pathology, Stony Brook University, Stony Brook, New York 11794, USA [2] Institute of Molecular Oncology, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: U M
authors.initials: UM
authors.lastname: Moll
mesh_terms: D000483:Alleles; D064591:Allografts; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D055550:Protein Stability / Q000187:drug effects; D015996:Survival Rate; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D050505:Mutant Proteins; C533237:STA 9090; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases