TY - JOUR

T1 - Molecular response to PARP1 inhibition in ovarian cancer cells as determined by mass spectrometry based proteomics

AU - Franz, Alexandra

AU - Coscia, Fabian

AU - Shen, Ciyue

AU - Charaoui, Lea

AU - Mann, Matthias

AU - Sander, Chris

PY - 2021

Y1 - 2021

N2 - 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 beta-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-kappa B 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.

AB - 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 beta-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-kappa B 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.

KW - PARP inhibitors

KW - High-grade serous ovarian cancer

KW - Mass spectrometry based proteomics

KW - Molecular response profiling

KW - Pathway analysis

KW - Data-driven protein module discovery

KW - Molecular signaling pathways

KW - PARP inhibitor resistance

KW - Combination therapy

KW - OLAPARIB MAINTENANCE THERAPY

KW - POLY(ADP-RIBOSE) POLYMERASE-1

KW - LIPID-METABOLISM

KW - MECHANISMS

KW - RESISTANCE

KW - COMBINATION

KW - CARCINOMA

KW - RUCAPARIB

KW - LYMPHOMA

KW - REVEALS

U2 - 10.1186/s13048-021-00886-x

DO - 10.1186/s13048-021-00886-x

M3 - Journal article

C2 - 34686201

VL - 14

JO - Journal of Ovarian Research

JF - Journal of Ovarian Research

SN - 1757-2215

M1 - 140

ER -