Reference Detail

Ref Type Journal Article
PMID (26009011)
Authors Alexandrova EM, Yallowitz AR, Li D, Xu S, Schulz R, Proia DA, Lozano G, Dobbelstein M, Moll UM
Title Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.
Journal Nature
Vol 523
Issue 7560
Date 2015 Jul 16
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 L194F breast cancer sensitive Ganetespib Preclinical - Cell culture Actionable In a preclinical study, Ganetespib inhibited growth of human breast cancer cells harboring TP53 L194F in culture (PMID: 26009011). 26009011
TP53 R175H breast cancer sensitive Ganetespib Preclinical - Cell culture Actionable In a preclinical study, Ganetespib inhibited growth of human breast cancer cells harboring TP53 R175H in culture (PMID: 26009011). 26009011
TP53 R248Q Advanced Solid Tumor sensitive Ganetespib Preclinical Actionable In a preclinical study, Ganetespib extended survival by 48% in mice with tumors expressing TP53 R248Q (PMID: 26009011). 26009011
TP53 S241F ovarian cancer sensitive Ganetespib Preclinical Actionable In a preclinical study, Ganetespib inhibited growth of human ovarian cancer cells harboring TP53 S241F in culture (PMID: 26009011). 26009011
TP53 L194F breast cancer sensitive Tanespimycin + Vorinostat Preclinical - Cell line xenograft Actionable In a preclinical study, Tanespimycin (17-AAG) and Zolinza (vorinostat) were synergistic towards tumor growth inhibition in human breast cancer cell line xenograft models harboring TP53 L194F (PMID: 26009011). 26009011
TP53 R280K breast cancer sensitive Ganetespib Preclinical Actionable In a preclinical study, Ganetespib inhibited growth of human breast cancer cells harboring TP53 R280K in culture (PMID: 26009011). 26009011
TP53 L194F breast cancer sensitive Tanespimycin Preclinical - Cell line xenograft Actionable In a preclinical study, Tanespimycin (17-AAG) inhibited tumor growth in human breast cancer cell line xenograft models harboring TP53 L194F (PMID: 26009011). 26009011
TP53 L194F breast cancer sensitive Vorinostat Preclinical - Cell line xenograft Actionable In a preclinical study, Zolinza (vorinostat) inhibited tumor growth in human breast cancer cell line xenograft models harboring TP53 L194F (PMID: 26009011). 26009011
TP53 R175H Advanced Solid Tumor sensitive Alvespimycin + Vorinostat Preclinical Actionable In a preclinical study, Alvespimycin (17-DMAG) and Zolinza (vorinostat) extended survival by 59% in mice with tumors expressing Tp53 R172H (which corresponds to R175H in the human Tp53 protein) (PMID: 26009011). 26009011
TP53 P223L TP53 V274F prostate cancer resistant Ganetespib Preclinical Actionable In a preclinical study, Ganetespib inhibited growth of human prostate cancer cells harboring TP53 P223L and V274F in culture (PMID: 26009011). 26009011