DNA damage response pathways (DDR) (DDR)

The DNA damage response (DDR) pathways comprise a sophisticated network of signaling cascades and repair mechanisms that maintain genomic integrity by detecting and fixing DNA lesions [1]. In tumor cells, these pathways are frequently dysregulated, often characterized by the loss of specific repair components which leads to genomic instability and accelerated mutation rates [2]. This deficiency creates a therapeutic vulnerability known as synthetic lethality, where the inhibition of a compensatory repair pathway leads to selective cancer cell death [3]. For instance, PARP inhibitors are highly effective in tumors with BRCA1/2 mutations, as these cells cannot repair double-strand breaks via homologous recombination [4]. Beyond PARP, current drug development focuses on inhibiting other key DDR nodes such as ATR, ATM, and DNA-PK to sensitize tumors to chemotherapy and radiation [5]. These inhibitors work by preventing the repair of DNA damage induced by exogenous agents or endogenous processes, ultimately triggering apoptosis in cancer cells [3, 6]. Clinical success in this area depends heavily on identifying patient populations with specific genetic defects, such as ATM loss or HRD [6]. Understanding the specific DDR defects in a patient's tumor is crucial for the successful application of these targeted therapies [6].

Other names

DNA repair pathwaysDDR networkGenome stability pathwaysDNA damage signaling and repair

Inhibition of specific DNA repair enzymes (e.g., PARP, ATR, ATM) to induce synthetic lethality in repair-deficient cells or to sensitize cells to DNA-damaging agents [3, 6]