Abstract 3065: Modeling common aspects of the metabolic response of cancer cells to ionizing radiation
Authors: Adam Krysztofiak, Klaudia A. Szymonowicz, Julian Hlouschek, Christoph Waterkamp, Kexu Xiang, Daniel Hoffmann, Verena Jendrossek, Johann Matschke
Journal: Cancer Research (2021)

Abstract Flexibility and reprogramming of cancer metabolism supports cancer progression and therapy resistance. In previous work we described opportunities for overcoming environment-induced resistance to ionizing radiation (IR) by pharmacologic inhibition of metabolic processes [1,2,3]. Here, we hypothesized that certain aspects of cancer metabolism will support the repair of radiation-induced DNA double-strand breaks (DSBs) and that the identification of pathways critical to the repair of radiation-induced DNA damage and cell survival will allow to enhance sensitivity of cancer cells to IR by interfering with such metabolic liabilities. Yet little is known about metabolic aspects of the cancer cell response to IR. We therefore systematically screened a panel of cancer cell lines with distinct genetic backgrounds for time-dependent changes in their acute metabolic response to IR and recorded the kinetics of IR-induced DSB in parallel. Mathematical modelling of the obtained metabolic and radiobiological data revealed a common metabolic response of irradiated cancer cells with impact on the kinetics of DSB repair. These were characterized by a rapid but transient downregulation of glycolysis and mitochondrial respiration, and gradual reactivation of glycolysis prior to mitochondrial recovery, presumably to compensate for disturbed metabolic functions of impaired mitochondria. Application of fractionated IR doses retarded mitochondrial recovery, highlighting the inhibitory effects of IR on mitochondrial functions. Furthermore, combining IR with inhibitors of compensatory glycolysis slowed mitochondrial recovery and DNA repair kinetics, supporting the functional relevance of compensatory glycolysis for DNA repair. Mathematical modeling of the metabolic response to IR allowed us to generate new hypotheses on the metabolic requirements of irradiated cancer cells and potential associated metabolic vulnerabilities. Further mechanistic studies will reveal the role of oncogenic drivers and co-mutations in metabolic enzymes for metabolic flexibility and metabolic liabilities of irradiated cancer cells in support of personalized approaches for combinatorial treatments. [1] Matschke J, et al., Antioxid Redox Signal 2016; 25: 89-107. [2] Hlouschek J et al., Front Oncol 2018; 8: 170. [3] Hlouschek J et al., Cancer Lett 2018; 439: 24-38. Supported by grants of the DFG (GRK1739/2 to V.J. and MA 8970/1-1 to J.M.), the Deutsche Krebshilfe/Mildred Scheel-Stiftung (70112711 to V.J.). Citation Format: Adam Krysztofiak, Klaudia A. Szymonowicz, Julian Hlouschek, Christoph Waterkamp, Kexu Xiang, Daniel Hoffmann, Verena Jendrossek, Johann Matschke. Modeling common aspects of the metabolic response of cancer cells to ionizing radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3065.