DNA Damage Response in Cancer: Molecular Mechanisms and Therapeutic Exploitation

Abstract

The DNA damage response (DDR) represents a highly conserved network of signaling pathways and repair mechanisms that are crucial for preserving genomic integrity. Cancer, which is marked by extensive genomic instability, often develops due to inherited or acquired deficiencies within these pathways. Paradoxically, these very defects can make tumor cells susceptible to therapeutic approaches that target the systems they are unable to regulate effectively. This review offers a thorough synthesis of DDR mechanisms, their dysfunction in the context of oncogenesis, and the emerging paradigm of targeting DDR components in cancer treatment. Particular emphasis is placed on the notion of synthetic lethality and its clinical application through poly(ADP-ribose) polymerase (PARP) inhibitors in tumors with BRCA mutations. Additionally, we explore new resistance mechanisms, the influence of the tumor microenvironment, and future prospects for functional biomarkers and personalized therapeutic strategies.