@article{8cc1cc7989d54c8e9c0f2d0027768614,
title = "Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer",
abstract = "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.",
keywords = "ESRRA, chemoradiation, esophageal cancer, metabolic reprogramming, oxidative phosphorylation, radiation, resistance",
author = "Dings, {Mark P.G.} and {van der Zalm}, {Amber P.} and Sanne Bootsma and {van Maanen}, {Tatum F.J.} and Cynthia Waasdorp and {van den Ende}, Tom and Dajia Liu and Peter Bailey and Jan Koster and Zwijnenburg, {Danny A.} and Spek, {C. Arnold} and Klomp, {Jan P.G.} and Arthur Oubrie and Meijer, {Sybren L.} and {van Berge Henegouwen}, {Mark I.} and Hulshof, {Maarten C.} and Jacques Bergman and Cesar Oyarce and Medema, {Jan Paul} and {van Laarhoven}, {Hanneke W.M.} and Bijlsma, {Maarten F.} and Hooijer, {Gerrit K. J.}",
note = "Funding Information: J.P.M. has acted as a consultant to AbbVie. M.I.v.B.H. served as consultant for Johnson and Johnson, Medtronic, Alesi Surgical, and Mylan and has received unrestricted research funding from Stryker and Olympus. A.O. and J.P.G.K. are employees of Lead Pharma. Lead Pharma owns two patent applications (WO 2021/001453 A1 and WO 2021/074365 A1) claiming the invention of ERRa inverse agonists. The compounds described in these patent applications are not chemically related to the compound described in this manuscript. Funding Information: M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma and has acted as a consultant to Servier. H.W.M.v.L. has a consultant or advisory role with Amphera, AstraZeneca, Beigene, BMS, Daiichy-Sankyo, Dragonfly, Eli Lilly, MSD, Nordic Pharma, and Servier; has received research funding and/or medication supply from Bayer, BMS, Celgene, Janssen, Incyte, Eli Lilly, MSD, Nordic Pharma, Philips, Roche, and Servier; and has a speaker role with Astellas, Benecke, Daiichy-Sankyo, JAAP, Medtalks, Novartis, and Travel Congress. Management B.V Employment and leadership: Amsterdam UMC, the Netherlands (head of the Department of Medical Oncology) Honorary: ESMO (chair Upper GI faculty). Funding Information: We thank the patients for participating. We thank Arlene Oei and Hans Rodermond for their help with the in vivo radiation setup. This work was supported by Oncode funding (to J.P.M.) and a KWF Dutch Cancer Society project grant ( 10992/2017-1 ) (to M.F.B. and H.W.M.v.L.). Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = nov,
day = "15",
doi = "https://doi.org/10.1016/j.xcrm.2022.100802",
language = "English",
volume = "3",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "11",
}