Oncometabolites and the response to radiotherapy

Abstract

Radiotherapy (RT) is applied in 45-60% of all cancer patients either alone or in multimodal therapy concepts comprising surgery, RT and chemotherapy. However, despite technical innovations approximately only 50% are cured, highlight a high medical need for innovation in RT practice. RT is a multidisciplinary treatment involving medicine and physics, but has always been successful in integrating emerging novel concepts from cancer and radiation biology for improving therapy outcome. Currently, substantial improvements are expected from integration of precision medicine approaches into RT concepts. Altered metabolism is an important feature of cancer cells and a driving force for malignant progression. Proper metabolic processes are essential to maintain and drive all energy-demanding cellular processes, e.g. repair of DNA double-strand breaks (DSBs). Consequently, metabolic bottlenecks might allow therapeutic intervention in cancer patients. Increasing evidence now indicates that oncogenic activation of metabolic enzymes, oncogenic activities of mutated metabolic enzymes, or adverse conditions in the tumor microenvironment can result in abnormal production of metabolites promoting cancer progression, e.g. 2-hyroxyglutarate (2-HG), succinate and fumarate, respectively. Interestingly, these so-called "oncometabolites" not only modulate cell signaling but also impact the response of cancer cells to chemotherapy and RT, presumably by epigenetic modulation of DNA repair. Here we aimed to introduce the biological basis of oncometabolite production and of their actions on epigenetic regulation of DNA repair. Furthermore, the review will highlight innovative therapeutic opportunities arising from the interaction of oncometabolites with DNA repair regulation for specifically enhancing the therapeutic effects of genotoxic treatments including RT in cancer patients.

Tumor Hypoxia Drives Genomic Instability

“…Specifically, hypoxic exposure downregulates genes involved in DNA replication and repair pathways, thus increasing genomic instability ( Hassan Venkatesh et al, 2020 ). Interestingly, tumor hypoxia can epigenetically regulate DNA DSB repair by inducing the accumulation of oncometabolites, such as succinate, fumarate, 2-hydroxyglutarate (2-HG) and D -2-hydroxyglutarate, which are competitive inhibitors of the αKG-dependent KDM and TET families of epigenetic enzymes that function in DSB repair pathways like HRR and NHEJ ( Xiang et al, 2020 ).…”

A New Twist in Protein Kinase B/Akt Signaling: Role of Altered Cancer Cell Metabolism in Akt-Mediated Therapy Resistance

“…Among those, especially metformin, rotenone, malonate, atovaquone, hydrocortisone and oligomycin are promising examples (for a more detailed discussion see [ 227 , 228 ]). However, the most interesting target in the TCA cycle is IDH1/2: IDH1/2 is frequently mutated in aggressive cancers and contributes to various aspects of malignant growth, including also epigenetic regulation of DSB repair [ 22 , 230 ]. Drugs targeting both IDH isoforms have already been approved for cancer treatment [ 231 , 232 ].…”

“…Consequently, cells have also evolved a cellular response to ROS to counteract ROS-mediated damage cellular by activation of antioxidant systems [ 17 , 18 ]. Importantly, recent reports support a requirement of metabolic activity and certain metabolites to fuel the DDR, as well as antioxidant defense and DSB repair [ 19 , 20 , 21 , 22 ].…”

“…Of note, the ability of cancer cells to mount an efficient DDR and the high capacity of cancer cells to repair radiation-induced lethal DNA lesions promotes radioresistance, and this can be exploited therapeutically [ 1 , 23 ]. Increased basal activation of the DDR or increased antioxidant capacity can also contribute to increased radiation resistance [ 22 , 24 , 25 ]. In fact, DDR, DSB repair and cellular antioxidant defense systems are recognized as important targets for improving the outcome of cancer (radio)therapy [ 9 , 24 , 26 , 27 , 28 , 29 , 30 ].…”

“…However, oncogene-induced and stress-induced metabolic reprogramming emerged as an additional important hallmark of cancer [ 31 ]. Notably, the resulting metabolic plasticity affects the primary cancer response to therapy and also supports adaptive therapy resistance, including treatments involving radiotherapy [ 22 , 24 , 32 , 33 ]. Vice versa, the frequent occurrence of defects in DDR and DSB repair pathways in various cancers offers opportunities for synthetic lethality approaches by inhibition of complementary DSB repair pathways [ 34 , 35 , 36 , 37 , 38 ].…”