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

Abstract

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.

Figure 1

The effects of radiation-induced DNA damage. A, Major types of radiation-induced DNA damage with respective DNA damage sensor proteins are illustrated. Radiation induces single-strand breaks (SSB) either directly or indirectly as intermediates of base excision repair. Simple double-strand breaks (DSB) involve two broken DNA ends in close proximity and occur in euchromatin (EC). Complex DSBs involve two broken DNA ends (i.e. 2-ended DSB) in proximity to additional DNA damage (e.g. cross-links, SSBs, etc.) or within heterochromatin (HC), or a DSB within a replication fork (1-ended DSB). B, SSBs and simple DSBs are repaired with fast kinetics by SSB repair and non-homologous end-joining (NHEJ) pathways, respectively. Alternative-end-joining (alt-EJ) is a slow, compensatory repair pathway activated when DNA-PKcs is absent or when NHEJ/HR attempt, but fail to complete repair. Alt-EJ likely contributes to repair of complex 2-ended DSBs. Homologous recombination (HR) operates under slow kinetics and is partly responsible for repair of complex 2-ended DSBs and exclusively responsible for repair of 1-ended DSBs. These repair pathways function in a cell cycle dependent manner, as illustrated. C, Cell cycle checkpoints are activated in response to DNA damage to prevent propagation of cells with damaged DNA and to permit time for DNA repair. The major checkpoints include those occurring in G1, S and G2. While ATM activation is the initial response to radiation-induced DNA DSBs, ATR is subsequently activated and contributes to a sustained cell cycle checkpoint response. Dashed lines represent incompletely understood pathways. Other abbreviations: ATRIP, ATR interacting protein; MRN, Mre11-Rad50-Nbs1