Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition

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

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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.

Original languageEnglish
Pages (from-to)779-786
Number of pages8
JournalNature Chemical Biology
Volume12
Issue number10
DOIs
Publication statusPublished - Oct 2016
Externally publishedYes

Cite this

Boudreau, A., Purkey, H. E., Hitz, A., Robarge, K., Peterson, D., Labadie, S., ... O'Brien, T. (2016). Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nature Chemical Biology, 12(10), 779-786. https://doi.org/10.1038/nchembio.2143
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, Alexander N. ; Williams, Simon ; Daemen, Anneleen ; Belvin, Marcia ; Eigenbrot, Charles ; Jackson, Peter K. ; Malek, Shiva ; Hatzivassiliou, Georgia ; Sampath, Deepak ; Evangelista, Marie ; O'Brien, Thomas. / Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. In: Nature Chemical Biology. 2016 ; Vol. 12, No. 10. pp. 779-786.
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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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Boudreau, A, Purkey, HE, Hitz, A, Robarge, K, Peterson, D, Labadie, S, Kwong, M, Hong, R, Gao, M, Del Nagro, C, Pusapati, R, Ma, S, Salphati, L, Pang, J, Zhou, A, Lai, T, Li, Y, Chen, Z, Wei, B, Yen, I, Sideris, S, McCleland, M, Firestein, R, Corson, L, Vanderbilt, AN, Williams, S, Daemen, A, Belvin, M, Eigenbrot, C, Jackson, PK, Malek, S, Hatzivassiliou, G, Sampath, D, Evangelista, M & O'Brien, T 2016, 'Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition', Nature Chemical Biology, vol. 12, no. 10, pp. 779-786. https://doi.org/10.1038/nchembio.2143

Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. / 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, Alexander N.; Williams, Simon; Daemen, Anneleen; Belvin, Marcia; Eigenbrot, Charles; Jackson, Peter K.; Malek, Shiva; Hatzivassiliou, Georgia; Sampath, Deepak; Evangelista, Marie; O'Brien, Thomas.

In: Nature Chemical Biology, Vol. 12, No. 10, 10.2016, p. 779-786.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Zhou, Aihe

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AU - Li, Yingjie

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Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D, Labadie S et al. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nature Chemical Biology. 2016 Oct;12(10):779-786. https://doi.org/10.1038/nchembio.2143