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PDBsum entry 4zvv
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4zvv
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References listed in PDB file
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Key reference
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Title
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Metabolic plasticity underpins innate and acquired resistance to ldha inhibition.
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Authors
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A.Boudreau,
H.E.Purkey,
A.Hitz,
K.Robarge,
D.Peterson,
S.Labadie,
M.Kwong,
R.Hong,
M.Gao,
C.Del nagro,
R.Pusapati,
S.Ma,
L.Salphati,
J.Pang,
A.Zhou,
T.Lai,
Y.Li,
Z.Chen,
B.Wei,
I.Yen,
S.Sideris,
M.Mccleland,
R.Firestein,
L.Corson,
A.Vanderbilt,
S.Williams,
A.Daemen,
M.Belvin,
C.Eigenbrot,
P.K.Jackson,
S.Malek,
G.Hatzivassiliou,
D.Sampath,
M.Evangelista,
T.O'Brien.
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Ref.
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Nat Chem Biol, 2016,
12,
779-786.
[DOI no: ]
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PubMed id
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Abstract
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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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