RT Journal Article
SR Electronic
T1 Translational and HIF1α-dependent metabolic reprograming underpin oncometabolome plasticity and synergy between oncogenic kinase inhibitors and biguanides
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 160879
DO 10.1101/160879
A1 Laura Hulea
A1 Simon-Pierre Gravel
A1 Masahiro Morita
A1 Marie Cargnello
A1 Oro Uchenunu
A1 Young Kyuen Im
A1 Shannon McLaughlan
A1 Ola Larsson
A1 Michael Ohh
A1 Tiago Ferreira
A1 Celia Greenwood
A1 Gaëlle Bridon
A1 Daina Avizonis
A1 Josie Ursini-Siegel
A1 Julie St-Pierre
A1 Michael Pollak
A1 Ivan Topisirovic
YR 2017
UL http://biorxiv.org/content/early/2017/07/07/160879.abstract
AB There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI – biguanide combinations is impeded by HIF1α and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1α-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.