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摘要 : 肿瘤抑制因子TP53 是人类癌症中最常发生突变的基因之一。虽然一些基因改变会使其完全丧失,但很多基因改变都是功能获得性突变,在其中突变体 p53蛋白获得会促进肿瘤发生的新功能。

 肿瘤抑制因子TP53 是人类癌症中最常发生突变的基因之一。虽然一些基因改变会使其完全丧失,但很多基因改变都是功能获得性突变,在其中突变体 p53蛋白获得会促进肿瘤发生的新功能。Ute Moll及同事现在通过一个小鼠模型显示,这样一个p53突变体的表达不仅是肿瘤起始所需的,而且是肿瘤维持所需的。他们进而显示,他们能够通过抑制一个被称为Hsp90的伴侣分子(该分子是保持突变体p53蛋白稳定所需的)来间接定位突变体p53。在一个淋巴瘤小鼠模型中,该方法导致了突变体p53的降解和肿瘤生长的减小。


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


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.

来源: Nature 浏览次数:1


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