Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition

  • Nat Chem Biol. 2016 Oct;12(10):779-86. doi: 10.1038/nchembio.2143.
Aaron Boudreau  1 ,  Hans E Purkey  2 ,  Anna Hitz  3 ,  Kirk Robarge  2 ,  David Peterson  1 ,  Sharada Labadie  2 ,  Mandy Kwong  3 ,  Rebecca Hong  3 ,  Min Gao  3 ,  Christopher Del Nagro  3 ,  Raju Pusapati  1 ,  Shuguang Ma  4 ,  Laurent Salphati  4 ,  Jodie Pang  4 ,  Aihe Zhou  2 ,  Tommy Lai  5 ,  Yingjie Li  6 ,  Zhongguo Chen  6 ,  Binqing Wei  2 ,  Ivana Yen  7 ,  Steve Sideris  7 ,  Mark McCleland  8 ,  Ron Firestein  8 ,  Laura Corson  3 ,  Alex Vanderbilt  9 ,  Simon Williams  9 ,  Anneleen Daemen  10 ,  Marcia Belvin  3 ,  Charles Eigenbrot  11 ,  Peter K Jackson  3 ,  Shiva Malek  7 ,  Georgia Hatzivassiliou  3 ,  Deepak Sampath  3 ,  Marie Evangelista  1 ,  Thomas O'Brien  3
Affiliations
  • 1. Discovery Oncology, Genentech, South San Francisco, California, USA.
  • 2. Discovery Chemistry, Genentech, South San Francisco, California, USA.
  • 3. Translational Oncology, Genentech, South San Francisco, California, USA.
  • 4. Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California, USA.
  • 5. Chemistry, WuXi AppTec Co., Ltd., Shanghai, China.
  • 6. Structural Biology, WuXi AppTec Co., Ltd., Shanghai, China.
  • 7. Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, USA.
  • 8. Department of Pathology, Genentech, South San Francisco, California, USA.
  • 9. Biomedical Imaging, Genentech, South San Francisco, California, USA.
  • 10. Bioinformatics, Genentech, South San Francisco, California, USA.
  • 11. Structural Biology, Genentech, South San Francisco, California, USA.
PMID: 27479743 DOI: 10.1038/nchembio.2143
Abstract

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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