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

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 and Joan S. Brugge ()
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Ioannis K. Zervantonakis: Ludwig Center at Harvard, Harvard Medical School
Claudia Iavarone: Ludwig Center at Harvard, Harvard Medical School
Hsing-Yu Chen: Ludwig Center at Harvard, Harvard Medical School
Laura M. Selfors: Ludwig Center at Harvard, Harvard Medical School
Sangeetha Palakurthi: Dana Farber Cancer Institute
Joyce F. Liu: Dana Farber Cancer Institute
Ronny Drapkin: University of Pennsylvania School of Medicine
Ursula Matulonis: Dana Farber Cancer Institute
Joel D. Leverson: Oncology Development, AbbVie, Inc
Deepak Sampath: Translational Oncology, Genentech
Gordon B. Mills: MD Anderson Cancer Center
Joan S. Brugge: Ludwig Center at Harvard, Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00263-7

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