ESTRO 2022 - Abstract Book

S307

Abstract book

ESTRO 2022

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SP-0353 Preservation of mitochondrial integrity participates in radioresistance in head and neck mouse cancer models

P. Sonveaux 1 , D. Grasso 1

1 University of Louvain (UCLouvain) Medical School, Pole of Pharmacology and Therapeutics, Brussels, Belgium

Abstract Text The clinical management of head and neck squamous cell carcinoma (HNSCC) commonly involves chemoradiotherapy, but recurrences often occur that are associated with radioresistance. Using human SQD9 laryngeal squamous cell carcinoma cancer cells as a model, we aimed to identify metabolic changes associated with acquired radioresistance. In a top-down approach, matched radiosensitive and radioresistant SQD9 cells were generated and metabolically compared, focusing on glycolysis, oxidative phosphorylation (OXPHOS) and ROS production. The cell cycle, clonogenicity, tumor growth in mice and DNA damage-repair were assessed. Mitochondrial DNA (mtDNA) was sequenced. In a bottom-up approach, matched glycolytic and oxidative SQD9 cells were generated using FACS-sorting, and tested for their radiosensitivity/radioresistance. We found that acquired radioresistance is associated with a shift from a glycolytic to a more oxidative metabolism in SQD9 cells. The opposite was also true, as the most oxidative fraction isolated from SQD9 wild-type cells was also more radioresistant than the most glycolytic fraction. However, neither reduced hexokinase expression nor OXPHOS were directly responsible for the radioresistant phenotype. Radiosensitive and radioresistant cells had similar proliferation rates and were equally efficient for ATP production. They were equally sensitive to redox stress and had similar DNA damage repair, but radioresistant cells had an increased number of mitochondria and a higher mtDNA content. Thus, an oxidative switch is associated with but is not responsible for acquired radioresistance in human SQD9 cells. In radioresistant cells, more and fitter mitochondria could help to preserve mitochondrial functions upon irradiation.

SP-0354 Cross-talk of radiotherapy-induced mitochondrial impairment and resulting metabolic reprogramming impact DNA DSB repair capacity

J. Matschke 1

1 Institute of Cell Biology (Cancer Research), University Hospital Essen, Essen, Germany

Abstract Text 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 Sk ł odowska-Curie Innovative Training Program THERADNET (MSCA ITN (ETN) THERADNET (Grant Agreement No. 860245) and the the Federal Ministry of Education and Research (BMBF, 02NUK061B)

Symposium: Radiotherapy in head and neck advanced disease in surgery with reconstruction area

SP-0355 What is an optimal target in reconstructed tissue? W. Budach Germany