Molecular response to PARP1 inhibition in ovarian cancer cells as determined by mass spectrometry based proteomics

Alexandra Franz,Matthias Mann,Ciyue Shen,Fabian Coscia,Chris Sander,Lea Charaoui

doi:10.1186/s13048-021-00886-x

Abstract

BackgroundPoly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood.MethodsHere, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment.ResultsWe found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, consistent with transcript changes in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and β-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-κB signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for therapeutic inhibition in combination with PARP1i. When tested experimentally, the combination of PARPi with an inhibitor of fatty acid synthase (TVB-2640) has a 3-fold synergistic effect and is therefore of particular pre-clinical interest.ConclusionOur study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.

Highlights

(ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood
To gain insight into the molecular processes induced by the inhibition of PARP1 protein in HGSOC, we treated HGSOC Ovsaho cells with a potent inhibitor AG-14361 that selectively inhibits the PARP1 protein (Ki < 5 nM) [26], and measured the protein response profile by unbiased mass spectrometry (MS) based-proteomics
Molecular processes associated with PARP1i cytotoxicity or resistance Based on the function of identified protein network modules in proliferative processes and the protein expression change of module members, we evaluated whether PARP1i-responsive processes could promote cytotoxicity or resistance

Summary

Introduction

(ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. Other indications for treatment with PARPi include patients with mutations in other HR pathway components (e.g., BRIP1, PALB2, FANCD2) [9]. Other models suggest that due to the diverse roles of PARP proteins in the DNA repair response, PARPi-induced deficiencies in other DNA repair pathways may contribute to tumor sensitivity to PARPi [12]. A more recent model is the ‘trapping’ of PARP proteins at DNA damage sites during DNA replication, leading to replication collapse, the accumulation of unresolved DSBs and eventually to cell death [13, 14]

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Results

Discussion

Conclusion