Metabolic induction of DNA repair defects for improving the outcome of radiotherapy.

• Applicant: Dr. Johann Matschke
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442358541

Balancing redox-homeostasis and energy metabolism allows cancer cells exposed to chemotherapy or radiotherapy to ensure DNA repair and survival. Our previous work revealed that adaptive changes in antioxidant defense and cancer cell metabolism not only enhance cancer cell radioresistance but also create metabolic dependencies that are amenable to therapeutic intervention for overcoming adaptive radioresistance. The proposed project aims to identify further metabolic dependencies with impact on the capacity of cancer cells to repair radiation-induced lethal DNA lesions in order to define tumor-specific therapeutic targets for increasing radiosensitivity and improving patient outcome in combinatorial treatments. We recently identified the mitochondrial citrate carrier protein SLC25A1 as a critical regulator of mitochondrial redox homeostasis and energy metabolism with impact on DNA repair and the survival of irradiated cancer cells. Genetic or pharmacologic inhibition of SLC25A1 not only affected mitochondrial function and redox homeostasis but also induced accumulation of 2-HG. Interestingly, other groups reported that oncogene-dependent or hypoxia-induced accumulation of 2-hydroxyglutarate (2HG) affects the repair of radiation-induced DNA damage by homologous recombination repair (HRR) and thereby renders cancer cells vulnerable to treatment with inhibitors of end-joining dependent DNA repair pathways. We thus hypothesize that SLC25A1 inhibition creates a “drug-induced HR-ness” phenotype in HRR-proficient cancer cells by inducing the accumulation of 2HG and 2HG-dependent inhibition of HRR, potentially involving epigenetic mechanisms. However, the mechanisms connecting SLC25A1 deficiency and accumulation of 2HG are not fully understood. Moreover, the functional relevance of 2HG-accumulation for compromised DNA repair upon SLC25A1-inhibition remains to be demonstrated. Furthermore, potential interactions between genetic, environmental and pharmacological drivers of 2HG-accumulation and their impact on DNA repair and radiation sensitivity remain to be explored. Finally, despite the documented role of SLC25A1 in radioresistance, the proposed concept of drug-induced HR-ness and synthetic lethality with ionizing radiation and pharmacologic inhibition of alternative DNA repair pathways has to be validated in a broader range of solid tumors, focusing on tumor entities with frequent up-regulation of SLC25A1 expression. These open questions will be addressed in the proposed project.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Tomer Shlomi