Inhibition of the non homologous end joining process in the context of hypoxic tumor cells

Radiotherapy and most of the antineoplastic drugs induce directly or not the formation of DNA damage among which double strand breaks (DSBs) represent the major toxic lesion. The presence of DSBs triggers the DNA damage response (DDR), an interconnected network that maintains cell viability and genomic stability. Consequently, the inhibition of DDR is considered as a potential target for cancer treatment. The DDR response comprises cell signaling and DNA repair pathways. Since the non homologous end-joining (NHEJ) pathway represents the major process responsible for DSBs repair, it represents a challenging target, and inhibitors are under therapeutic evaluation. However, tumor cells grow under hypoxia, an environmental stress inducer of an adaptive response regulated by the transcriptional heterodimer named hypoxia inducible factor (HIF). HIF regulates a wide variety of target genes involved in cell metabolism and neovascularization, but also in DNA repair. In this review, the cross-talk between HIF and DNA repair factors is examined in the context of cancer treatment with inhibitors of the NHEJ pathway.