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- Title
Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response.
- Authors
Zervantonakis, Ioannis K.; Iavarone, Claudia; Hsing-Yu Chen; Selfors, Laura M.; Palakurthi, Sangeetha; Liu, Joyce F.; Drapkin, Ronny; Matulonis, Ursula; Leverson, Joel D.; Sampath, Deepak; Mills, Gordon B.; Brugge, Joan S.
- Abstract
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.
- Subjects
OVARIAN cancer; BCL-2 proteins; SYSTEM analysis; CELL death; DRUG resistance; DRUGS; DRUG resistance in cancer cells
- Publication
Nature Communications, 2017, Vol 8, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-00263-7