Introduction 

Ionising radiation induces DNA damage primarily through the formation of single and double strand breaks which, if unrepaired, can lead to cell death. These breaks activate the DNA damage response. (DDR) which is a network of cellular pathways that detect and repair any DNA damage and includes the phosphorylation of proteins like H2AX and DNA-PK. When damage is extensive or incorrectly repaired, this can result in genomic instability, apoptosis, or senescence. In drug discovery, this mechanism can be exploited by combining targeted delivery of ionising radiation to cancer cells with inhibition of key DDR proteins, thereby preventing repair and promoting tumour cell death.

Biomarkers of radiosensitivity and DNA damage are therefore critical for both preclinical and clinical evaluation of novel combination therapies.