Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer

Specific metabolicunderpinnings of androgen receptor (AR)-driven growth in prostate adenocarcinoma(PCa) are largely undefined, hindering the development of strategies to leverage the metabolicdependencies of this disease when hormonal manipulations fail. Here we show that the mitochondrial pyruvate carrier (MPC), a critical metabolicconduit linking cytosolic and mitochondrial metabolism, is transcriptionally regulated by AR. Experimental MPC inhibition restricts proliferation and metabolicoutputs of the citric acid cycle(TCA) including lipogenesisand oxidative phosphorylationin AR-driven PCa models. Mechanistically, metabolicdisruption resulting from MPC inhibition activates the eIF2α/ ATF4 integrated stress response(ISR). ISR signalling prevents cell cycle progression while coordinating salvage efforts, chiefly enhancing glutamine assimilation into the TCA, to regain metabolichomeostasis. We confirm that MPC function is operant in PCa tumours in vivo using isotopomeric metabolic flux analysis. In turn, we apply a clinically viable small molecule targeting the MPC, MSDC0160, to pre-clinical PCa models and find that MPC inhibition suppresses tumour growth in hormone-responsive and castrate-resistant conditions. Collectively, our findings characterize the MPC as a tractable therapeutic target in AR-driven prostate tumours.