Imperial College London


Faculty of MedicineDepartment of Surgery & Cancer




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BibTex format

author = {Barnes, EME and Xu, Y and Benito, A and Herendi, L and Siskos, AP and Aboagye, EO and Keun, H and Nijhuis, A},
doi = {10.1038/s41416-020-0777-y},
journal = {British Journal of Cancer},
pages = {1298--1308},
title = {Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells},
url = {},
volume = {122},
year = {2020}

RIS format (EndNote, RefMan)

AB - BackgroundAkt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition.MethodsThe effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry.ResultsLactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib.ConclusionsLactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.
AU - Barnes,EME
AU - Xu,Y
AU - Benito,A
AU - Herendi,L
AU - Siskos,AP
AU - Aboagye,EO
AU - Keun,H
AU - Nijhuis,A
DO - 10.1038/s41416-020-0777-y
EP - 1308
PY - 2020///
SN - 0007-0920
SP - 1298
TI - Lactic acidosis induces resistance to the pan-Akt inhibitor uprosertib in colon cancer cells
T2 - British Journal of Cancer
UR -
UR -
UR -
VL - 122
ER -