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

Article

关键词: MOUSE MODEL;    HSP90 COMPLEX;    CANCER-CELLS;    IN-VITRO;    GAIN;    GANETESPIB;    INHIBITOR;    GELDANAMYCIN;    METASTASIS;    SPECTRUM;   

DOI  :  10.1038/nature14430

来源: SCIE

【 摘 要 】

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(1-5). Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities(6-8). 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(9-12). We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele(2)) and H/H (R172H allele(3)) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) (also known as Trp53(-/-)) 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.

【 授权许可】

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