Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hürthle cell carcinoma of the thyroid

Abstract

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 H&uumlrthle 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 PDX 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.

BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer

“…This observation strongly suggests that it’s necessary to either identify the cancer type/patients suitable for the treatment, or optimize the treatment regimen to reduce the side effects of targeting complex I. Indeed, complex I loss exposes fermentation as a therapeutic target in hurthle cell carcinoma and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration 50, 51 . We herein show that BET inhibition on the one hand has a strong negative impact on glycolysis, on another hand increases GDH1-mediated glutamine metabolic remodeling, establishing a synthetic lethality to target both pathways.…”

“…This observation strongly suggests that it's necessary to either identify the cancer type/patients suitable for the treatment, or optimize the treatment regimen to reduce the side effects of targeting complex I. Indeed, complex I loss exposes fermentation as a therapeutic target in hurthle cell carcinoma and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration 50,51 .…”