Resistance To Ldha Inhibitors Requires Signaling Through The Ampk/Mtor/S6k Pathway Leading To Increased Oxidative Phosphorylation

Lactate Dehydrogenase A (LDHA) is an attractive candidate for targeting glycolysis-addicted tumors. However, due to the inherent plasticity of metabolic networks in cells, there is concern that the benefit of targeting LDHA may be transient and that resistance will quickly emerge. To identify predictive features of LHDA inhibitor sensitivity and to understand how cells adapt to long-term LHDA inhibition, we screened a large panel (∼500) of tumor cell lines with GNE-140, a newly developed LHDA inhibitor. We found that approximately 15% of lines were inherently sensitive to the LDHA inhibitor, with sensitivity correlating with increased expression of glycolysis genes and inversely correlating with expression of oxidative phosphorylation genes. Despite the metabolic plasticity of cells, the timing of acquired resistance to LDHA inhibitors was comparable with other targeted agents. Under long-term LDHAi treatment, glycolytic cells acquired resistance by increased oxidative phosporylation (OX-PHOS) in a mechanism dependent on the AMPK stress response pathway; targeting either AMPK, downstream kinases, or OX-PHOS using tool compounds synergized with and prevented acquired resistance to GNE-140. Taken together, our data suggests that targeting anaerobic glycolysis may benefit a subset of patients across indications and that combinations with agents that block AMPK signaling or the mitochondria will be effective at delaying tumor relapse. Citation Format: Aaron Boudreau, David Peterson, John Moffat, Bonnie Liu, Mandy Kwong, Min Gao, Hans Purkey, Thomas O9Brien, Georgia Hatzivassiliou, Anneleen Daemen, Marie Evangelista. Resistance to LDHA inhibitors requires signaling through the AMPK/mTOR/S6K pathway leading to increased oxidative phosphorylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1423. doi:10.1158/1538-7445.AM2014-1423