PO-119 Accelerated glutamine metabolism is conferring radioresistance to prostate cancer

Introduction Pathophysiological conditions within the tumour microenvironment induce metabolic adaptations of cancer cells. These metabolic features correlating with aggressive tumour growth pattern and the relapse risk after radiotherapy. Beside glucose, fast-growing cancer cells consume glutamine for energy production. Within the presented project we investigated the potential of the glutamine metabolism as putative therapeutic target and predictive biomarker for an individualised radiotherapy of prostate cancer (PC) patients. Material and methods Genome and metabolome analysis of radioresistant PC cells identified the glutamine metabolism as regulator for intrinsic sensitivity to irradiation. Radiosensitizing effects of glutamine deprivation, molecular targeting and genetic suppression of key enzymes were determined for clonogenic survival, DNA repair and sphere-formation ability to determine the cancer stem cell (CSC) potential in PC cell lines, primary culture models and ex vivo treated primary biopsies. Analysis of tumour growth after glutamine deprivation were performed in xenograft models. The intracellular level of the glutamine metabolism and tricarboxylic acid cycle metabolites, reactive oxygen species (ROS) and glutathione (GSH) were determined. The clinical validation of the identified metabolic biomarkers was carried out with the NanoString technology. Results and discussions Radioresistant PC cells exhibit an accelerated glutaminolysis with enhanced α-ketoglutarate to succinate ratio. The elevated α-ketoglutarate is leading to GSH consumption, increased intracellular ROS level, modulated epigenetic regulators and induction of a CSC phenotype. Metabolic, chemical and genetic targeting of glutaminolysis results in the inhibition of mTOR signalling, enhanced endoplasmic reticulum stress and reduction of DNA repair. In combination with irradiation this targeting therapy is effectively radiosensitizing PC cells in vitro and in vivo . Moreover, the c-MYC gene expression, a key regulator of glutaminolysis, significantly correlates with the PSA-free survival after radiotherapy. Conclusion This study shows that the enhanced glutaminolysis of PC cells is conferring resistance to radiotherapy. The therapeutic targeting of the glutamine metabolism is elevating the cytotoxic effects of irradiation. In addition, metabolic enzymes involved in the glutamine metabolism can be potentially used to predict clinical outcome of PC patients after radiotherapy.