Systems analysis of apoptotic priming in ovarian cancer identifies vulnerabilities and predictors of drug response
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Ioannis K Zervantonakis1, Claudia Iavarone1, Hsing-Yu Chen1
1Department of Cell Biology, Ludwig Center at Harvard, Harvard Medical School, Boston, MA, 02115, USA.
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.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.
Insights
Targeting apoptosis regulators can improve treatment for high-grade serous ovarian cancer (HGS-OvCa). This study reveals how inhibiting PI3K/mTOR pathway regulators can overcome drug resistance in HGS-OvCa tumors.
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- High-grade serous ovarian cancer (HGS-OvCa) often develops resistance to conventional chemotherapy.
- Effective alternative treatment strategies are urgently needed for HGS-OvCa.
Purpose of the Study:
- To investigate HGS-OvCa patient-derived xenografts for sensitivity to PI3K and PI3K/mTOR inhibitors.
- To uncover cell death vulnerabilities and mechanisms of drug resistance.
- To identify novel therapeutic targets by analyzing apoptotic regulators.
Main Methods:
- Utilized a systems-approach to analyze 14 HGS-OvCa patient-derived xenografts (PDXs).
- Performed proteomic analysis to study signaling responses to PI3K/mTOR inhibition.
- Conducted quantitative analysis of BCL-2 family proteins and apoptotic regulators.
- Employed computational modeling and selective anti-apoptotic protein inhibitors.
Main Results:
- PI3K/mTOR inhibition in HGS-OvCa PDXs induced both pro-apoptotic and anti-apoptotic signaling.
- These responses limited direct cell killing but primed cells for inhibitors of anti-apoptotic proteins.
- Identified specific apoptotic regulators (BIM, caspase-3, BCL-XL, MCL-1, XIAP) predictive of drug sensitivity and resistance.
- Uncovered mechanistic details of apoptotic regulation in HGS-OvCa.
Conclusions:
- A systems-approach can systematically analyze mechanisms limiting tumor cell killing.
- Targeting apoptosis regulators can overcome drug resistance in HGS-OvCa.
- This strategy holds potential for improving treatment outcomes in ovarian and other cancers.
