High-grade serous carcinoma (HGSC) is the most frequently diagnosed and aggressive form of ovarian cancer that presents with poor clinical outcomes long-term. Despite the initial success of current treatments, such as platinum-based chemotherapies and poly (ADP-ribose) polymerase (PARP) inhibitors, patients often relapse, highlighting the need for more effective maintenance therapies. Arginine deprivation therapies, such as administration of the enzymatic drug ADI-PEG20, target tumour metabolism by removing extracellular sources of arginine that cancer cells rely on for growth and proliferation and has been shown to be especially effective in cells deficient in the rate-limiting enzyme of arginine biosynthesis, argininosuccinate synthase (ASS1).

Analyses were performed on CRISPR/Cas9-edited ID8 murine ovarian epithelial models with TP53-loss, PTEN-loss and ASS1-deficiency. The bulk metabolomes of ADI-PEG20-treated or arginine-starved ID8 lines/omental tumours were analysed by liquid chromatography-mass spectrometry (LC-MS). Treatment-related growth inhibition was assayed using SRB and compared between PTEN-wild type/loss models. The effects of arginine starvation on mTOR signalling and DNA repair response proteins were measured by western blotting analysis.

Arginine deprivation via ADI-PEG20 treatment or medium starvation induces global metabolic changes impacting several pathways including polyamine biosynthesis, one-carbon metabolism, choline metabolism and glutamine metabolism. Arginine starvation induced suppression of mTOR signalling and DNA repair response factors, suggesting mechanisms by which arginine deprivation may inhibit tumour growth and induce cell death differentially according to PTEN status when combined with the PARP inhibitor Olaparib.

These findings highlight the potential for arginine deprivation therapies in treating genetically defined subsets of ovarian carcinoma, particularly in combination with clinically approved agents that interfere with DNA repair such as PARP inhibitors.