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Title:
Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response | Nature Communications
Description:
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.
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nature portfolio scientific editing privacy policy dual pan-pi3-kinase/mtor inhibitors advertising combination index pi3k/akt/mtor pathway activation15 pi3k-Ξ±/Ξ³/Ξ΄ inhibitor phosphoinositide 3-kinase/akt/mammalian target social media pi3k/akt/mtor pathway activation nature nature 474 nature 527 ovarian cancer research reprints pulsed bcl-2/bcl-xl inhibitor selective pi3k/akt/mtor inhibitors pi3k/akt/mtor pathway targets bcl-2/bcl-xl inhibition enhances bcl-xl-specific inhibitor combinations bcl-2/bcl-xl inhibitor combination translational cancer research applied cancer research bcl-2/bcl-xl drug combination pi3k/mtor-based combination therapies high bcl-xl levels anti-apoptotic proteins bcl-xl targeted therapy development dual pi3k/mtor inhibitor bcl-2/bcl-xl combination treatment dual pi3k/mtor inhibition fibroblast-related prognostic signature phospho-4ebp1 protein levels matrix-attached cancer cells cancer genome atlas bcl-xl protein levels patient-derived cancer cells author information authors pi3k/akt/mtor axis pi3k/akt/mtor pathway ras/erk pathway activity pan-pi3k inhibitor pictilisib phosphoinositide-3-kinase antagonist aezs-126 phospho-akts473 protein levels pi3k/mtor-inhibition induces real-time therapy tailoring iccb-longwood screening facility pi3k/akt activation status single-cell expression profiles
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- Cancer Systems Biology: a peek into the future of patient care?
- Potential of apoptotic pathway-targeted cancer therapeutic research: Where do we stand?
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headline:Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response
description: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.
datePublished:2017-08-28T00:00:00Z
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Cancer therapeutic resistance
Ovarian cancer
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