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

Abstract

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.

cAMP-Dependent Signaling and Ovarian Cancer

“…One of the promising therapeutic perspectives is the use of DNA-dependent nuclear enzymes, such as poly(adenosine diphosphate-ribose) polymerase (PARP) [ 160 ]. PARP are the main enzymes activated in the response to DNA damage [ 161 ]. Currently, PARP inhibitors (PARPi) are used in first-line, second-line, or maintenance therapy after platinum-based chemotherapy [ 162 , 163 ].…”

IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation

“…We previously reported that peripheral TCR analysis and early ctDNA dynamics could predict clinical response to ICIs [32]. Franz et al reported that the clinical utility of proteomic analysis may clarify the responders to PAPRi [33]. Given the additional effect of PAPRi for modulating the tumor microenvironment and cancer-specific T cells, our combined novel analysis could identify the subgroup that shows a good response to this combination therapy.…”

Metabolic reprogramming of clear cell renal cell carcinoma

“…In a phase I clinical trial, TVB-2640 effectively reduced fatty acid production in patients with non-small cell lung cancer. In subsequent clinical trials for breast and ovarian cancer, TVB-2640 exhibited favorable clinical activity and safety, with no gastrointestinal or serum toxicity observed ( 101 , 102 ). Adverse events were mainly mild and included skin and eye effects, which were manageable with appropriate measures.…”