TY - JOUR T1 - Translational and HIF1α-dependent metabolic reprograming underpin oncometabolome plasticity and synergy between oncogenic kinase inhibitors and biguanides JF - bioRxiv DO - 10.1101/160879 SP - 160879 AU - Laura Hulea AU - Simon-Pierre Gravel AU - Masahiro Morita AU - Marie Cargnello AU - Oro Uchenunu AU - Young Kyuen Im AU - Shannon McLaughlan AU - Ola Larsson AU - Michael Ohh AU - Tiago Ferreira AU - Celia Greenwood AU - Gaëlle Bridon AU - Daina Avizonis AU - Josie Ursini-Siegel AU - Julie St-Pierre AU - Michael Pollak AU - Ivan Topisirovic Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/07/07/160879.abstract N2 - 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. ER -