Low level of antioxidant capacity biomarkers but not target overexpression predicts vulnerability to ROS-inducing drugs

Despite a strong rationale for why cancer cells are susceptible to redox-targeting drugs, such drugs often face tumor resistance or dose-limiting toxicity in preclinical and clinical studies. An important reason is the lack of specific biomarkers to better select susceptible cancer entities and stratify patients. Using a large panel of lung cancer cell lines, we identified a set of antioxidant-capacity biomarkers (ACB), which were tightly repressed, partly by STAT3 and STAT5A/B in sensitive cells, rendering them susceptible to multiple redox-targeting and ferroptosis-inducing drugs. Contrary to expectation, constitutively low ACB expression was not associated with an increased steady state level of reactive oxygen species (ROS) but a high level of nitric oxide, which is required to sustain high replication rates. Using ACBs, we identified cancer entities with a high percentage of patients with favorable ACB expression pattern, making it likely that more responders to ROS-inducing drugs could be stratified for clinical trials.

Automated summary

A study found a set of antioxidant-capacity biomarkers (ACB) in lung cancer cell lines, which are repressed by STAT3 and STAT5A/B in sensitive cells, making them susceptible to redox-targeting and ferroptosis-inducing drugs. Low ACB expression was associated with a high level of nitric oxide instead of reactive oxygen species (ROS), which is required for high replication rates. ACB expression pattern can help stratify cancer patients for clinical trials of ROS-inducing drugs.