Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response

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

来源：Nature Communications, 2017, 8(1): 365.

DOI：10.1038/s41467-017-00263-7

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.

• 出版日期2017-8-28