Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid

• Published in: Cancer discovery Vol. 13; no. 8; pp. 1884 - 1903
• Main Authors: Frank, Anderson R, Li, Vicky, Shelton, Spencer D, Kim, Jiwoong, Stott, Gordon M, Neckers, Leonard M, Xie, Yang, Williams, Noelle S, Mishra, Prashant, McFadden, David G
• Format: Journal Article
• Language: English
• Published: United States 04.08.2023
• Subjects: Adenocarcinoma; Adenoma, Oxyphilic - genetics; Carcinoma; DNA, Mitochondrial - genetics; Fermentation; Humans; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-22-0982

A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration. HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects. See related article by Gopal et al., p. 1904. This article is highlighted in the In This Issue feature, p. 1749.