DNA Damage Response and Cancer Treatment

Abstract

Throughout long-term evolution, cells have evolved sophisticated defence systems to counteract DNA damage, which are essential for preserving genomic stability and ensuring proper cellular function. The DNA damage response (DDR) is a complex network of cellular pathways that detect, signal, and repair DNA lesions to preserve genomic integrity. In cancer cells, these mechanisms are often dysregulated, leading to genomic instability—a hallmark of cancer. Paradoxically, this vulnerability also presents a therapeutic opportunity. This review explores the dual role of DDR in cancer development and treatment, highlighting the molecular pathways involved, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR). Recent advancements in targeting DDR pathways have led to the development of novel therapies, such as PARP inhibitors, ATM/ATR inhibitors, and CHK1/CHK2 inhibitors, which selectively exploit defects in cancer cell repair mechanisms while sparing normal cells. We also discuss the concept of synthetic lethality and its application in precision oncology. Furthermore, we examine resistance mechanisms to DDR-targeted therapies and potential strategies to overcome them. The integration of DDR-targeted agents with immunotherapy and conventional treatments is also considered. This review underscores the critical importance of DDR in cancer biology and treatment, offering insights into how manipulating these pathways can lead to more effective and personalized cancer therapies.