LAUSR

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with less than 10% of patients surviving 5-years from diagnosis. Arginine deprivation using pegylated arginine deiminase (ADI-PEG20) is a novel treatment for mesothelioma deficient in the arginine biosynthetic enzyme ASS1. However, resistance to ADI-PEG20 in MPM is a significant problem and is characterized in part by reprogramming of the urea and polyamine metabolism pathway (Locke et al., 2016). We sought to identify a targeted metabolism-based therapy to overcome the emerging resistance and increase the efficiency of ADI-PEG20 treatment for patients with MPM. New models of ADI-PEG20 resistance were generated by constant exposure of MPM cell lines to arginine deprivation for 6 months. ADI-PEG20 resistant and sensitive MPM cell lines were treated with a panel of polyamine targeting molecules. Metabolome alterations were studied by targeted metabolomics and glucose flux analyses. Our results confirmed the up-regulation of ASS1 expression from (50 to 3000-fold) alongside upregulation of polyamine catabolism and upon generation of ADI-PEG20 resistance. Treatment of ADI-PEG20 resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20 resistant cell lines were significantly more sensitive to the spermidine-analogue GC7 than their respective ASS1-ve parental cell lines. Moreover, the combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. We observed a significant synergistic effect of GC7 and ADI-PEG20 in both ASS1-ve and ASS1+ve cell lines in 2D and 3D cell culture models as well as in our mice in vivo model. Metabolomics analysis revealed that GC7 treatment significantly impaired the TCA cycle. We hypothesize that GC7 is repurposing the fate of Acetyl-CoA to polyamine catabolism therefore shutting down the TCA cycle. Our findings provide novel insights into a polyamine targeted therapy that may prevent resistance to ADI-PEG20 treatment in MPM and related arginine-auxotrophic cancers. Citation Format: Joséphine Carpentier, Peter W. Szlosarek, Sarah Anne Martin. ADI-PEG20 and GC7 as a novel anti-metabolite strategy for the treatment of malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1760.