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 Mills, Joan S. Brugge

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Article number365
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Zervantonakis, I. K., Iavarone, C., Chen, H. Y., Selfors, L. M., Palakurthi, S., Liu, J. F., Drapkin, R., Matulonis, U., Leverson, J. D., Sampath, D., Mills, G., & Brugge, J. S. (2017). Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response. Nature Communications, 8(1), [365]. https://doi.org/10.1038/s41467-017-00263-7