The metabolic underpinnings of androgen receptor (AR)-driven growth in prostate cancer (PCa) are underexplored, hindering the development of strategies to leverage the metabolic properties differentiating PCa from normal tissue. To this end, we discovered a subunit of the mitochondrial pyruvate carrier (MPC), MPC2, is a direct AR target gene that is increased in PCa specimens and associated with clinical outcomes. Our observation suggests a targetable link between AR signaling and carbon trafficking in PCa. Indeed, MPC inhibition delays proliferation and alters metabolic properties in hormone sensitive and castrate resistant AR-driven PCa models. Next, using 13C metabolic flux analysis coupled with a reverse phase protein array, we determined MPC inhibition results in activation of the eIF2α/ATF4 integrated stress response pathway to partially compensate for MPC inhibition by coordinating increased glutamine incorporation into the citric acid cycle. Therefore, to amplify the effect of MPC inhibition, we restricted glutamine availability during MPC inhibition and found this combination resulted in proliferative arrest. Last, we extended our efforts in-vivo and demonstrated combinatorial MPC/glutaminase inhibition resulted in a significant reduction in castrate-resistant prostate tumor xenograft growth in mice with no overt host toxicity. We anticipate our findings will accelerate the development of clinical strategies to therapeutically manipulate carbon flux to starve clinically lethal castrate-resistant PCa.

Citation Format: David A. Bader, Nagireddy Putluri, Sean M. Hartig, Sean E. McGuire. Androgen receptor regulates the mitochondrial pyruvate carrier to fuel oncometabolism in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5431. doi:10.1158/1538-7445.AM2017-5431