Nuclear DNA in cancer cells with DNA damage-repair deficiencies (nDNA (DDRD))

Nuclear DNA in cancer cells with DNA damage-repair (DDR) deficiencies represents a critical therapeutic target that exploits the concept of synthetic lethality (Lord & Ashworth, 2017, Science). In healthy cells, multiple redundant pathways exist to repair various types of DNA damage, such as single-strand breaks and double-strand breaks (O'Connor, 2015, Molecular Cell). However, many cancers harbor mutations in key repair genes like BRCA1, BRCA2, or ATM, rendering them dependent on a limited set of functional repair mechanisms. By pharmacologically inhibiting these remaining pathways—most notably through PARP inhibitors—clinicians can induce an accumulation of unrepairable DNA damage specifically within the tumor cells, leading to apoptosis (Lord & Ashworth, 2017, Science). This strategy provides a high degree of selectivity, as normal cells with intact DDR pathways can survive the treatment. Beyond PARP inhibition, this target is also susceptible to DNA-damaging agents like platinum salts, which create lesions that DDR-deficient cells are uniquely unable to resolve (Kelland, 2007, Nature Reviews Cancer). Understanding the specific DDR deficiency is paramount for patient stratification, as the efficacy of these treatments is directly linked to the underlying genetic defect in the nuclear DNA (Pilié et al., 2019, Nature Reviews Clinical Oncology).

Other names

Genomic DNA in HRD cellsDDR-deficient nuclear DNATargeted DNA in synthetic lethalityBRCA-mutant genomic DNA

Exploitation of synthetic lethality through the inhibition of compensatory DNA repair pathways (e.g., PARP) or direct induction of DNA lesions (e.g., cross-links) that cannot be repaired due to specific pathway deficiencies.