卵巢癌凋亡与药物敏感性
  • 非偏倚性系统方法,采用一组14个注释的高度浆液性卵巢癌(HGS-OvCa)的患者来源异种移植瘤(PDX)模型;
  • 蛋白质组学分析揭示HGS-OvCa PDX模型内抑制PI3K/mTOR诱导促凋亡和抗凋亡信号传导应答,限制细胞杀伤,但启动细胞抑制抗凋亡蛋白质;
  • 对BCL-2家族蛋白质等进行深度定量分析,结合计算机模型和选择性抗凋亡蛋白质抑制剂,揭示凋亡调控的新机制,预测药物敏感性和耐药性;
  • 靶向凋亡调控因子可改善PI3K/mTOR通路抑制剂的疗效。
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Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response

系统性分析卵巢癌凋亡启动,鉴定出药物疗效的缺陷和预测因素

10.1038/s41467-017-00263-7

2017-08-28, Article

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The lack of effective chemotherapies for high-grade serous ovarian cancers (HGS-OvCa) has motivated a search for alternative treatment strategies. Here, we present an unbiased systems-approach to interrogate a panel of 14 well-annotated HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors and uncover cell death vulnerabilities. Proteomic analysis reveals that PI3K/mTOR inhibition in HGS-OvCa patient-derived xenografts induces both pro-apoptotic and anti-apoptotic signaling responses that limit cell killing, but also primes cells for inhibitors of anti-apoptotic proteins. In-depth quantitative analysis of BCL-2 family proteins and other apoptotic regulators, together with computational modeling and selective anti-apoptotic protein inhibitors, uncovers new mechanistic details about apoptotic regulators that are predictive of drug sensitivity (BIM, caspase-3, BCL-XL) and resistance (MCL-1, XIAP). Our systems-approach presents a strategy for systematic analysis of the mechanisms that limit effective tumor cell killing and the identification of apoptotic vulnerabilities to overcome drug resistance in ovarian and other cancers.High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance. Here, the authors through a systematic analysis of proteomic and drug response data of 14 HGS-OvCa PDXs demonstrate that targeting apoptosis regulators can improve response of these tumors to inhibitors of the PI3K/mTOR pathway.

First Authors:
Ioannis K Zervantonakis

Correspondence Authors:
Joan S Brugge

All Authors:
Ioannis K Zervantonakis,Claudia Iavarone,Hsing-Yu Chen,Laura M Selfors,Sangeetha Palakurthi,Joyce F Liu,Ronny Drapkin,Ursula Matulonis,Joel D Leverson,Deepak Sampath,Gordon B Mills,Joan S Brugge

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