Q1 · BIOLOGY
Article
Author: Hitz, Anna ; Pang, Jodie ; Ma, Shuguang ; Jackson, Peter K ; Pusapati, Raju ; Zhou, Aihe ; Salphati, Laurent ; Lai, Tommy ; Sideris, Steve ; McCleland, Mark ; Hatzivassiliou, Georgia ; Vanderbilt, Alex ; Belvin, Marcia ; Firestein, Ron ; Chen, Zhongguo ; Purkey, Hans E ; Robarge, Kirk ; Evangelista, Marie ; Hong, Rebecca ; O'Brien, Thomas ; Eigenbrot, Charles ; Labadie, Sharada ; Gao, Min ; Yen, Ivana ; Li, Yingjie ; Del Nagro, Christopher ; Corson, Laura ; Sampath, Deepak ; Malek, Shiva ; Wei, Binqing ; Kwong, Mandy ; Boudreau, Aaron ; Peterson, David ; Williams, Simon ; Daemen, Anneleen
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.