Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover.
Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover.
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DOI：
10.1101/gad.290122.116
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发表时间：
2016-12-15
影响因子：
10.5
通讯作者：
Elledge SJ
中科院分区：
文献类型：
--
作者：
Davoli T;Mengwasser KE;Duan J;Chen T;Christensen C;Wooten EC;Anselmo AN;Li MZ;Wong KK;Kahle KT;Elledge SJ
Davoli等人将核糖体蛋白翻译和蛋白酶体蛋白降解确定为PI 3 K驱动的肿瘤的关键非癌基因依赖性。他们的结果表明，通过核糖体或蛋白酶体抑制破坏蛋白质周转稳态可能是PI 3 K突变型人类肿瘤的一种新的治疗策略。磷酸肌醇3-激酶（PI 3 K）信号通路中的激活突变经常在癌症中发现。为了鉴定支持PI 3 K肿瘤发生的途径，我们在携带野生型或突变型PIK 3CA的同基因细胞系中进行了全基因组RNAi筛选，以寻找PI 3 K合成致死（SL）基因。将这些结果与PI 3 K突变癌细胞系中另外两个大规模RNAi筛选数据集的荟萃分析相结合，结果表明核糖体蛋白翻译和蛋白酶体蛋白降解是PI 3 K驱动肿瘤的关键非癌基因依赖性。基因或药理学抑制任一途径单独，但不一起，选择性地杀死PI 3 K突变肿瘤细胞的mTOR依赖性方式。核糖体和蛋白酶体组分的表达在具有PI 3 K通路激活的原发性人类结直肠肿瘤中显著上调。重要的是，在我们的荟萃分析中鉴定的含有SL基因的最高命中的PI 3 K SL基因签名有力地预测了结直肠癌患者的总体生存率，特别是在具有活化的PI 3 K通路的肿瘤患者中。这些结果表明，通过核糖体或蛋白酶体抑制破坏蛋白质周转稳态可能是PI 3 K突变型人类肿瘤的一种新的治疗策略。
Davoli et al. identified ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Their results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors. Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Genetic or pharmacologic inhibition of either pathway alone, but not together, selectively killed PI3K mutant tumor cells in an mTOR-dependent manner. The expression of ribosomal and proteasomal components was significantly up-regulated in primary human colorectal tumors harboring PI3K pathway activation. Importantly, a PI3K SL gene signature containing the top hits of the SL genes identified in our meta-analysis robustly predicted overall patient survival in colorectal cancer, especially among patients with tumors with an activated PI3K pathway. These results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors.