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	Vol	Issue	Date	Pages	Journal Short Title
Nature	523	7560	2015 Jul 16	352-6	Nature

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

Gene	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 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 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 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	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 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 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 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
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 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