Molecular Pathways: Overcoming Radiation Resistance by Targeting DNA Damage Response Pathways

DNA double-strand breaks are the critical lesions responsible for the majority of ionizing radiation-induced cell killing. Thus, the ability of tumor cells to elicit a DNA damage response following radiation, via activation of DNA repair and cell-cycle checkpoints, promotes radiation resistance and tumor cell survival. Consequently, agents that target these DNA damage response pathways are being developed to overcome radiation resistance. Overall, these agents are effective radiosensitizers; however, their mechanisms of tumor cell selectivity are not fully elucidated. In this review, we focus on the crucial radiation-induced DNA damage responses as well as clinical and translational advances with agents designed to inhibit these responses. Importantly, we describe how synthetic lethality can provide tumor cell-selective radiosensitization by these agents and expand the therapeutic window for DNA damage response-targeted agents used in combination with radiotherapy.