2. Academic Validation
  3. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition

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

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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