Background: Chondrosarcomas are malignant cartilage-producing tumors showing mutations and changes in gene expression in metabolism related genes. In this study, we aimed to explore the metabolome and identify targetable metabolic vulnerabilities in chondrosarcoma.
Methods: A custom-designed metabolic compound screen containing 39 compounds targeting different metabolic pathways was performed in chondrosarcoma cell lines JJ012, SW1353 and CH2879. Based on the anti-proliferative activity, six compounds were selected for validation using real-time metabolic profiling. Two selected compounds (rapamycin and sapanisertib) were further explored for their effect on viability, apoptosis and metabolic dependency, in normoxia and hypoxia. In vivo efficacy of sapanisertib was tested in a chondrosarcoma orthotopic xenograft mouse model.
Results: Inhibitors of glutamine, glutathione, NAD synthesis and mTOR were effective in chondrosarcoma cells. Of the six compounds that were validated on the metabolic level, mTOR inhibitors rapamycin and sapanisertib showed the most consistent decrease in oxidative and glycolytic parameters. Chondrosarcoma cells were sensitive to mTORC1 inhibition using rapamycin. Inhibition of mTORC1 and mTORC2 using sapanisertib resulted in a dose-dependent decrease in viability in all chondrosarcoma cell lines. In addition, induction of apoptosis was observed in CH2879 after 24 h. Treatment of chondrosarcoma xenografts with sapanisertib slowed down tumor growth compared to control mice.
Conclusions: mTOR inhibition leads to a reduction of oxidative and glycolytic metabolism and decreased proliferation in chondrosarcoma cell lines. Although further research is needed, these findings suggest that mTOR inhibition might be a potential therapeutic option for patients with chondrosarcoma.
Keywords: ACT, Atypical cartilaginous tumor; BLI, Bioluminescence imaging; BSA, Bovine serum albumin; BSO, Buthionine sulfoximine; Chondrosarcoma; D2HG, d-2-Hydroxyglutarate; DMSO, Dimethyl sulfoxide; ECAR, Extracellular acidification rate; FBS, Fetal bovine serum; FCCP, Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FLI, Fluorescence imaging; HIF, Hypoxia-inducible factor; IDH, Isocitrate dehydrogenase; Metabolism; OCR, Oxygen consumption rate; ROS, Reactive oxygen species; Rapamycin; mCT, Micro computed tomography; mTOR, Mammalian target of rapamycin; mTOR, Sapanisertib; α-KG, α-ketoglutarate.