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Molecular response to PARP1 inhibition in ovarian cancer cells as determined by mass spectrometry based proteomics
Alexandra Franz1,2,3, Fabian Coscia4, Ciyue Shen5,6,7
1Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02115, USA. afranz@ds.dfci.harvard.edu.
Background:
Poly (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.
Methods:
Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment.
Results:
We 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.
Conclusion:
Our 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.
Insights
Poly (ADP)-ribose polymerase 1 inhibitors (PARP1i) show promise in ovarian cancer treatment, but response mechanisms are unclear. This study reveals PARP1i triggers adaptive resistance via NF-κB signaling and lipid metabolism, suggesting combination therapies like fatty acid synthase inhibition for enhanced efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Poly (ADP)-ribose polymerase (PARP) inhibitors are standard treatment for high-grade serous ovarian cancer (HGSOC).
- The precise molecular mechanisms driving response and resistance to PARP1 inhibition (PARP1i) in HGSOC remain incompletely understood.
Purpose of the Study:
- To systematically characterize the proteomic response of HGSOC cells to PARP1 inhibition.
- To identify molecular mechanisms underlying treatment response and adaptive resistance to PARP1i.
- To nominate potential therapeutic targets for combination therapy with PARP1i.
Main Methods:
- Unbiased mass spectrometry-based proteomics was employed to analyze proteomic changes in HGSOC cells treated with PARP1i.
- Data-driven protein network analysis was used to interpret the proteomic alterations.
- Transcriptomic data from an independent perturbation dataset were used for validation.
Main Results:
- PARP1i induced significant proteomic alterations across diverse cellular processes in HGSOC cells.
- Decreased levels of SP1, β-catenin, and growth factor signaling indicated an anti-proliferative effect.
- Activation of NF-κB signaling and lipid metabolism suggested adaptive resistance mechanisms.
- Combination of PARPi with a fatty acid synthase inhibitor (TVB-2640) demonstrated a 3-fold synergistic anti-tumor effect.
Conclusions:
- This study enhances the understanding of PARP1 function beyond DNA repair in ovarian cancer.
- It highlights that anti-tumor efficacy of PARP1i may involve mechanisms independent of DNA damage repair.
- Findings inform the rational design of combination therapies to overcome resistance and improve treatment outcomes in ovarian cancer.
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