Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer

Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. Here, we delineate these resistance mechanisms. RNA sequencing on matched patient samples obtained pre-and post-neoadjuvant treatment reveal that oxidative phosphorylation was the most upregulated of all biological programs following nCRT. Analysis of patient-derived models confirms that mitochondrial content and oxygen consumption strongly increase in response to nCRT and that ionizing radiation is the causative agent. Bioinformatics identifies estrogen-related receptor alpha (ESRRA) as the transcription factor responsible for reprogramming, and overexpression and silencing of ESRRA functionally confirm that its downstream metabolic rewiring contributes to resistance. Pharmacological inhibition of ESRRA successfully sensitizes EAC organoids and patient-derived xenografts to radiation. In conclusion, we report a profound metabolic rewiring following chemoradiation and demonstrate that its inhibition resensitizes EAC cells to radiation. These findings hold broader relevance for other cancer types treated with radiation as well. [Display omitted] •Irradiated esophageal cancers upregulate oxidative phosphorylation components•ESRRA is activated by ROS and drives mitochondrial biogenesis•Inhibition of ESRRA sensitizes preclinical esophageal cancer models to radiation Dings et al. describe a novel metabolic rewiring in esophageal cancers treated with chemoradiation. Estrogen-related receptor alpha was identified as the mediator of an increased mitochondrial respiration following treatment, which conferred resistance. Inhibition of estrogen-related receptor alpha sensitizes cancer cells to (chemo)radiation in preclinical models for esophageal adenocarcinoma.