Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy
Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy
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DOI：
10.15252/msb.20188323
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发表时间：
2019-03-01
影响因子：
9.9
通讯作者：
Ruppin, Eytan
中科院分区：
文献类型：
--
作者：
Das Sahu, Avinash;Lee, Joo S.;Ruppin, Eytan
大多数晚期癌症患者最终会对靶向治疗产生耐药性，这促使人们做出广泛努力来确定介导治疗耐药性的分子事件。这些事件中的许多涉及合成拯救（SR）相互作用，其中由靶向基因失活引起的癌细胞活力的降低通过另一个基因（拯救者）的适应性改变而被拯救。在这里，我们通过分析10,000名TCGA癌症患者的肿瘤转录组学和生存数据，对SR拯救基因进行了全基因组的二氧化硅预测。预测的SR相互作用在新的实验屏幕验证。我们表明，SR相互作用可以成功地预测癌症患者的反应和新出现的耐药性。抑制预测的救援基因可协同地使耐药癌细胞对治疗敏感，为开发组合方法以主动克服耐药性提供初步线索。最后，我们表明，黑色素瘤患者的SR分析成功地确定了已知的免疫治疗抵抗介质，并预测新的救援。
Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silica prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.