DNA replication and repair response pathways (DDR pathways)

DNA replication and repair response pathways are essential cellular networks that maintain genomic integrity by identifying and correcting DNA lesions during the cell cycle. In the context of Tumor Treating Fields (TTFields), these pathways are significantly modulated; TTFields are low-intensity, intermediate-frequency alternating electric fields that disrupt the localization of highly polar proteins like tubulin and septins (Rominiyi et al., 2021, PMID: 33504550). Beyond physical disruption of mitosis, TTFields have been shown to downregulate the expression of critical DNA repair genes, particularly those in the Fanconi Anemia (FA) pathway and BRCA1, inducing a state of "BRCAness" in cancer cells (Kachel et al., 2019, PMID: 31110048). This downregulation leads to increased replication stress, delayed DNA damage repair, and enhanced sensitivity to DNA-damaging agents such as ionizing radiation and PARP inhibitors (Kari et al., 2022, PMID: 35454158). Clinically, this mechanism is exploited in the treatment of glioblastoma and mesothelioma, where TTFields are used as a regional therapy to promote mitotic catastrophe and apoptosis in rapidly dividing tumor cells while sparing quiescent healthy tissue (Novocure, 2024).

Other names

DNA damage responseDNA repair machineryTTFields-induced DNA damageFanconi Anemia pathway (as affected by TTFields)

TTFields exert physical forces on polar molecules to disrupt mitotic spindle assembly and downregulate the expression of DNA repair genes (e.g., BRCA1, FANCD2), leading to replication stress and impaired double-strand break repair.