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Boudreau, Aaron; Purkey, Hans E; Hitz, Anna; Robarge, Kirk; Peterson, David; Labadie, Sharada; Kwong, Mandy; Hong, Rebecca; Gao, Min; Del Nagro, Christopher; Pusapati, Raju; Ma, Shuguang; Salphati, Laurent; Pang, Jodie; Zhou, Aihe; Lai, Tommy; Li, Yingjie; Chen, Zhongguo; Wei, Binqing; Yen, Ivana; Sideris, Steve; McCleland, Mark; Firestein, Ron; Corson, Laura; Vanderbilt, Alex; Williams, Simon; Daemen, Anneleen; Belvin, Marcia; Eigenbrot, Charles; Jackson, Peter K; Malek, Shiva; Hatzivassiliou, Georgia; Sampath, Deepak; Evangelista, Marie; O'Brien, Thomas
Nature chemical biology, 10/2016, Volume: 12, Issue: 10Journal Article
Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.
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