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Repair of radiation-induced DNA damage is one of the 5 Rs of radiobiology and, in recent years, has been the subject of intense fundamental and translational research activity. Cancer cells frequently acquire a state of genomic instability, through mutational and non-mutational alterations in DNA repair pathways, as a means of driving clonal evolution and therapy resistance. While this state is associated with poor outcomes for patients, it also represents a therapeutic opportunity for oncologists who seek to exploit specific synthetically-lethal vulnerabilities in cancer cells with aberrant DNA repair capacity.

In this presentation, the basis of specific synthetically-lethal therapeutic strategies will be introduced and reviewed. At first, attempts to target cancer-specific vulnerabilities in combination with radiotherapy focused on the concept of tumour cell-specific radiosensitisation through the addition of small-molecule inhibitors with sensitisation enhancement ratios (SER) ranging between >1 and approximately 4. More recently, however, there has been a growing realisation that molecular radiosensitisation can also be associated with increased immune activation within the tumour microenvironment, and this might not necessarily require maximal exploitation of high-SER radiosensitisation.

The pathway involving ataxia telangiectasia and Rad3-related (ATR) kinase represents an excellent candidate for therapeutic exploitation. In this presentation, data on the true radiosensitising effects of ATR inhibition will be discussed. Subsequently, the pro-inflammatory effects of radiotherapy plus ATRi will be reviewed, focusing on published and unpublished data from preclinical studies of combinations with immune checkpoint blockade (anti-PD-L1, anti-TIGIT and anti-NKG2A antibodies). In addition, unpublished data on the immune effects of ATR inhibition (with ceralasertib, AZD6738) from our completed clinical PATRIOT trial will be presented.