Abstract 1016 Harnessing Redox Vulnerabilities for Cancer Precision Medicine with DNA Damage Response inhibitors

Non-small cell lung cancer (NSCLC) is the second most common cancer and the leading cause of cancer-related deaths worldwide, with a 5-year survival below 20% in patients with advanced disease. Many forms of NSCLC are refractory to current therapies, including radiotherapy and chemotherapy targeting DNA damage response (DDR). Although many DDR inhibitors, including PARP, ATM, and ATR inhibitors, have advanced in clinical trials, and are approved for treating other types of cancer, treatments targeting the DDR often encounter drug resistance when used as single agents, particularly in NSCLC. This drug resistance is caused by a metabolic rewiring that enables cancer cells to counteract a drug's most damaging effects. DNA repair genes and pathways are intrinsically involved in regulating bioenergetic metabolic pathways such as mitochondrial respiration, glycolysis, pentose phosphate pathway, and redox homeostasis. We recently utilized a metabolic CRISPR screen to identify genetic determinants of resistance to inhibitors of the DNA repair kinase ATM (Li et al, PNAS 2023). We demonstrated that NSCLC relies heavily on redox metabolism for survival upon ATM inhibition. However, the molecular crosstalk between genomic instability and metabolism remains poorly understood. Understanding these signaling pathways will help elucidate how cancer cells use metabolic reprogramming in response to DNA damage, possibly harnessing redox vulnerabilities to overcome resistance to DDR inhibitors. In this talk, I will highlight the most recent advances on redox vulnerabilities and precision medicine. I will discuss our newly established DDR-metabolism dependencies map, and the relevance to precision medicine with DDR inhibitors. Center for Cancer Research (CCR), NCI, NIH.