Abstract
Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
Highlights
Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology
It has been reported that multiple rounds of selection pressure at a dose that reduces survival to ~50% can enhance the sensitivity of genetic screens[23], the radiation dose that killed 50% of cells by clonogenic survival analysis (2 Gy) was used for these experiments
Results from our screen showed an enrichment of TMEM173/STING KO, suggesting that STING loss enhances cell survival in the setting of DNA damage
Summary
Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. We demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents. Until recently genome-wide screens in mammalian cells have typically utilized RNA interference (RNAi) based methodologies These approaches are limited, frequently with partial target suppression or off-target effects that lead to false-positive or negative results[10,11]. Using genome-wide CRISPRCas[9] screening we have made the unexpected discovery that STING loss alters redox homeostasis in tumor cells, identifying STING as an actionable target for reducing therapeutic resistance
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