Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
Vulnerabilities of PTEN-TP53-deficient prostate cancers to compound PARP-PI3K inhibition.
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DOI：
10.1158/2159-8290.cd-13-0230
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发表时间：
2014-08
期刊：
影响因子：
28.2
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
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作者：
González-Billalabeitia E;Seitzer N;Song SJ;Song MS;Patnaik A;Liu XS;Epping MT;Papa A;Hobbs RM;Chen M;Lunardi A;Ng C;Webster KA;Signoretti S;Loda M;Asara JM;Nardella C;Clohessy JG;Cantley LC;Pandolfi PP
前列腺癌（CaP）是男性中最常见的癌症，晚期的治疗选择有限。PTEN和p53肿瘤抑制基因的缺失通常在CaP中观察到，而它们的复合缺失通常在晚期CaP中观察到。这里我们表明，PARP抑制在PTEN缺乏的前列腺中引发p53依赖的细胞衰老。令人惊讶的是，我们还发现parp诱导的细胞衰老在PTEN和p53的复合丧失后演变为凋亡反应。我们进一步表明，促生存信号通路PI3K- akt通路的过度激活限制了PARP单药治疗的效果，并且PARP和PI3K抑制剂有效协同抑制人类CaP细胞系和Pten/p53缺陷小鼠晚期CaP模型的肿瘤发生。因此，我们的研究结果确定了PARP和PI3K抑制剂联合治疗是Pten缺陷CaP的有效选择。
Prostate cancer (CaP) is the most prevalent cancer in males and treatment options are limited for advanced forms of the disease. Loss of the PTEN and p53 tumor suppressor genes is commonly observed in CaP, while their compound loss is often observed in advanced CaP. Here we show, that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the pro-survival signalling PI3K-AKT pathway limits the efficacy of a PARP-single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human CaP cell lines and in a Pten/p53 deficient mouse model of advanced CaP. Our findings therefore identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient CaP.