Overcoming Resistance in DDR Inhibition: New Targets and Therapeutic Strategies

The field of DNA damage response (DDR) and repair inhibition has garnered significant attention due to its critical role in maintaining genomic stability and its implications in cancer development. Defects in DDR and repair pathways can lead to genomic instability, which is a hallmark of cancer and various other diseases. Despite decades of research that have elucidated numerous DDR and repair mechanisms, new players and pathways continue to be discovered. There are at least five major DNA repair pathways—base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ)—involving over 200 proteins that protect our genome. However, cancer cells often modulate the expression of these DNA repair proteins to gain mutational and survival advantages. This modulation opens up the possibility of using synthetic lethality strategies to target cancer cells, as demonstrated by the development of PARP inhibitors for BRCA-deficient cancers. Nevertheless, resistance to PARP inhibitors remains a significant challenge, necessitating the identification of novel cancer targets and structural insights for better precision medicine or combination therapies. Recent advances, such as cryo-EM, have provided structural insights into complex protein assemblies, revealing new therapeutic potentials. Integrating data from RNAi screening, CRISPR screening, and cancer genomic databases with known DDR pathways could uncover more effective cancer targets with synthetic lethal interactions.

This research topic aims to spark ideas and provide new findings and insights on the next breakthrough cancer targets for DNA damage response and repair inhibition. The goal is to explore novel cancer targets, structural insights, and innovative therapeutic strategies to overcome resistance and improve precision medicine. This topic collection invites all types of articles, including perspectives, reviews, original research, and methods, to contribute to this evolving field.

To gather further insights into the boundaries of DDR and repair inhibition, we welcome articles addressing, but not limited to, the following themes:

- Structural, computational, and functional research of DDR and repair mechanisms
- Development of DDR and repair inhibitors
- Discovery of novel DDR and repair proteins, cancer targets, and biomarkers
- Advanced methods for screening synthetic lethal
interactions and cancer genomic analysis in DDR
- (Pre)Clinical applications involving DDR and repair inhibitors