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.
Highlights
DNA Double-Strand Break RepairRadioresistance remains a major cause of treatment failure, leading to lower progression-free survival rates in cancers such as lung cancer, pancreatic cancer, and glioblastoma
More than half of cancer patients receive radiotherapy as a part of their cancer treatment
This failure indicates the necessity to investigate the underlying network of signal transduction pathways known as DNA damage response (DDR) pathways, which stimulate the repair of double-strand breaks (DSBs), the most lethal type of DNA damage due to radiotherapy [1]
Summary
Radioresistance remains a major cause of treatment failure, leading to lower progression-free survival rates in cancers such as lung cancer, pancreatic cancer, and glioblastoma. Cellular p53 regulates the expression of cell cycle regulators such as p21 that, through interaction with the cyclin-dependent kinase (CDK) complex, lead to G1 arrest Along with this process, chromatin modification occurs, and DNA repair is initiated [6]. It is notable that the described functions of these pathways in DSB repair and radioresistance are not solely dependent on IR-induced stimulation of the underlying pathways These cascades can become hyperactivated in tumor cells expressing mutations or overexpressing certain oncogenes or tumor suppressor genes, elevating the DSB repair capacity of these cells. As depicted, this mode of action in DSB repair may lead to the radioresistance of tumor cells Likewise, it provides a rationale for mutational screening and expression analyses of previously described oncogenes before radiotherapy. The information regarding the described signaling cascades is accompanied by a description of proof-of-principle radiosensitization by targeting the components of the described pathway
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