Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.
Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.
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DOI：
10.1038/nature14430
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发表时间：
2015-07-16
期刊：
影响因子：
64.8
通讯作者：
Moll UM
中科院分区：
文献类型：
--
作者：
Alexandrova EM;Yallowitz AR;Li D;Xu S;Schulz R;Proia DA;Lozano G;Dobbelstein M;Moll UM
p53 中的错义突变会产生具有消除肿瘤抑制功能的异常蛋白，这些蛋白还可以获得致癌功能获得性 (GOF)，从而促进恶性进展、侵袭、转移和化疗耐药。突变的 p53 (mutp53) 蛋白在肿瘤中经历大量的组成性稳定，这是 GOF 的关键必要条件。尽管目前全球有 1100 万患者患有表达高度稳定的 mutp53 的肿瘤，但尚不清楚 mutp53 是否是体内治疗靶点。在这里，我们使用表达不可激活的 R248Q 热点突变 (floxQ) 的新型 mutp53 小鼠模型来表明肿瘤依赖于持续的 mutp53 表达。在他莫昔芬诱导的 mutp53 消融后，同种异体移植肿瘤和本土肿瘤抑制其生长，从而使动物存活率延长 37%，晚期肿瘤发生细胞凋亡和肿瘤消退或停滞。与正常组织相比，HSP90/HDAC6 伴侣机制在癌症中显着上调，是 mutp53 稳定的主要决定因素。我们发现，长期 HSP90 抑制可显着延长 mutp53 Q/−2 和 H/H（R172H 等位基因）小鼠的存活率，分别延长 59% 和 48%，但对它们各自的 p53−/− 同窝小鼠则不然。这种 mutp53 依赖性药物效应发生在用 17DMAG+SAHA 治疗的 H/H 小鼠以及用强效 Hsp90 抑制剂 ganetespib 治疗的 H/H 和 Q/− 小鼠中。值得注意的是，药物活性与诱导 mutp53 降解、肿瘤细胞凋亡和预防 T 淋巴瘤发生相关。这些原理验证数据将 mutp53 确定为可操作的癌症特异性药物靶点。
Missense mutations in p53 generate aberrant proteins with abrogated tumor suppressor functions that can also acquire oncogenic gain-of-functions (GOF) that promote malignant progression, invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumors, which is the key requisite for GOF. Although currently 11 million patients worldwide live with tumors 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 inactivatible R248Q hotspot mutation (floxQ) to show that tumors depend on sustained mutp53 expression. Upon Tamoxifen-induced mutp53 ablation, allo-transplanted and autochthonous tumors curb their growth, thus extending animal survival by 37%, and advanced tumors undergo apoptosis and tumor regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared to normal tissues, is a major determinant of mutp53 stabilization. We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/−2 and H/H (R172H allele) mice by 59% and 48%, respectively, but not their respective 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, tumor apoptosis and prevention of T-lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.