Targeting the DNA Damage Response Machinery for Lung Cancer Treatment

Lung cancer is considered the most commonly diagnosed cancer and one of the leading causes of death globally. Despite the responses from small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients to conventional chemo- and radiotherapies, the current outcomes are not satisfactory. Recently, novel advances in DNA sequencing technologies have started to take off which have provided promising tools for studying different tumors for systematic mutation discovery. To date, a limited number of DDR inhibition trials have been conducted for the treatment of SCLC and NSCLC patients. However, strategies to test different DDR inhibitor combinations or to target multiple pathways are yet to be explored. With the various biomarkers that have either been recently discovered or are the subject of ongoing investigations, it is hoped that future trials would be designed to allow for studying targeted treatments in a biomarker-enriched population, which is defensible for the improvement of prognosis for SCLC and NSCLC patients. This review article sheds light on the different DNA repair pathways and some of the inhibitors targeting the proteins involved in the DNA damage response (DDR) machinery, such as ataxia telangiectasia and Rad3-related protein (ATR), DNA-dependent protein kinase (DNA-PK), and poly-ADP-ribose polymerase (PARP). In addition, the current status of DDR inhibitors in clinical settings and future perspectives are discussed.

Automated summary

Lung cancer is a frequently diagnosed cancer and a leading cause of death worldwide. Current treatment outcomes for small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients are unsatisfactory. DNA sequencing technologies have shown promise in studying tumor mutations. However, limited trials have been conducted for DDR inhibition in SCLC and NSCLC, and further exploration of combination therapies and targeting multiple pathways is needed. The review article discusses DNA repair pathways and inhibitors targeting proteins in the DDR machinery, such as ATR, DNA-PK, and PARP, as well as the current status and future perspectives of DDR inhibitors in clinical settings.