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Cancer bioenergetics fuel processes necessary to maintain viability and growth under stress conditions and thus contribute to therapy resistance. We hypothed that cancer metabolism supports the repair of radiation-induced DNA double-strand breaks (DSBs). We combined the systematic collection of metabolic and radiobiological data from a panel of irradiated cancer cell lines with mathematical modeling and identified a common metabolic response with impact on the DSB repair kinetics. These included i) a common transient mitochondrial shutdown that occurred independently of the genetic background, ii) a common activation of compensatory glycolysis, and iii) a delayed recovery of mitochondrial activity. Resumption of mitochondrial activity was influenced by oncogenic KRAS and loss or mutation of p53. Inhibition of compensatory glycolysis during IR-induced mitochondrial shutdown affected resumption of mitochondrial function and this was associated with delayed DNA repair and increased levels of residual DNA damage foci.
Combining systematic radiobiological investigations with mathematical modeling of the obtained results represents an innovative approach for the discovery of mechanisms supporting survival of irradiated cancer cells and thereby to reveal novel therapeutic targets.

Acknowledgement: Supported by grants of the DFG (MA8970/1-1), the European Commission under the Horizon 2020 Marie Skłodowska-Curie Innovative Training Program THERADNET (MSCA ITN (ETN) THERADNET (Grant Agreement No. 860245) and the the Federal Ministry of Education and Research (BMBF, 02NUK061B)