Targeting DNA Double-Strand Break Repair Pathways to Improve Radiotherapy Response

Abstract

More than half of cancer patients receive radiotherapy as a part of their cancer treatment. DNA double-strand breaks (DSBs) are considered as the most lethal form of DNA damage and a primary cause of cell death and are induced by ionizing radiation (IR) during radiotherapy. Many malignant cells carry multiple genetic and epigenetic aberrations that may interfere with essential DSB repair pathways. Additionally, exposure to IR induces the activation of a multicomponent signal transduction network known as DNA damage response (DDR). DDR initiates cell cycle checkpoints and induces DSB repair in the nucleus by non-homologous end joining (NHEJ) or homologous recombination (HR). The canonical DSB repair pathways function in both normal and tumor cells. Thus, normal-tissue toxicity may limit the targeting of the components of these two pathways as a therapeutic approach in combination with radiotherapy. The DSB repair pathways are also stimulated through cytoplasmic signaling pathways. These signaling cascades are often upregulated in tumor cells harboring mutations or the overexpression of certain cellular oncogenes, e.g., receptor tyrosine kinases, PIK3CA and RAS. Targeting such cytoplasmic signaling pathways seems to be a more specific approach to blocking DSB repair in tumor cells. In this review, a brief overview of cytoplasmic signaling pathways that have been reported to stimulate DSB repair is provided. The state of the art of targeting these pathways will be discussed. A greater understanding of the underlying signaling pathways involved in DSB repair may provide valuable insights that will help to design new strategies to improve treatment outcomes in combination with radiotherapy.

Keywords: double-strand break repair; ionizing radiation; molecular targeting; radiosensitization; signal transduction.

Figure 1

Cytoplasmic signaling cascades mediate post-irradiation cell survival and radioresistance in tumor cells by stimulating the canonical DSB repair pathways in the nucleus. Downstream effectors of cytoplasmic signaling cascades translocate to the nucleus and stimulate the canonical DSB repair pathway through either direct physical interaction with the repair protein or indirect stimulation of the pathway. IR: ionizing radiation; DSB: double-strand break; NHEJ: non-homologous end joining; HR: homologous recombination.

Figure 2

Overview of potential mechanisms by which epidermal growth factor (EGFR) stimulates DNA double-strand break repair, leading to radioresistance. (A) Ionizing radiation (IR) stimulates membrane-bound EGFR, which may lead to translocation of the receptor to the nucleus. Ionizing radiation may induce the activation of EGFR directly in the nucleus. (B) Exogenous stimulation of EGFR by related ligands, such as EGF and transforming growth factor α (TGFα), as well as autocrine secretion of EGFR ligands, such as in tumor cells harboring the KRAS mutation, induce nuclear translocation of EGFR. Following irradiation, activated EGFR in the nucleus stimulates DNA repair machinery by stimulating the phosphorylation/activation of proteins involved in DNA damage response (DDR) and DSB repair. EGFR may also function as a transcription factor regulating proteins involved in DSB repair.

Figure 3

AKT1 stimulates DSB repair through the NHEJ and HR repair pathways. Exposure to IR induces the activation of cytoplasmic AKT1 that may translocate to the nucleus. Alternatively, IR can activate AKT1 by stimulating nuclear receptor tyrosine kinases (RTKs) independent of cytoplasmic AKT1. Activated AKT1 in the nucleus stimulates the DNA repair machinery by increasing the expression of repair proteins such as Mre11 and Rad51 or inducing the phosphorylation/activation of proteins involved in DDR and DSB repair.