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Cancer Res. 2019 Aug 12. pii: canres.3959.2018. doi: 10.1158/0008-5472.CAN-18-3959. [Epub ahead of print]

Dual inhibition of GLUT1 and the ATR/CHK1 kinase axis displays synergistic cytotoxicity in KRAS-mutant cancer cells.

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Department I of Internal Medicine, University Hospital Cologne
Department I of Internal Medicine, University Hospital Cologne.
Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne.
Department of General, Visceral and Vascular surgery, Charité Universitätsmedizin Berlin.
Department II of Internal Medicine, University Hospital Cologne.
Institute of Diagnostic and Interventional Radiology, University Hospital Cologne.
Department of Radiology, University Hospital Cologne.
Department of Anesthesiology and Intensive Care Medicine, Translational Pain Research.


The advent of molecularly-targeted therapeutic agents has opened a new era in cancer therapy. However, many tumors rely on non-druggable cancer-driving lesions. In addition, long-lasting clinical benefits from single-agent therapies rarely occur, as most of the tumors acquire resistance over time. The identification of targeted combination regimens interfering with signaling through oncogenically rewired pathways provides a promising approach to enhance efficacy of single-agent targeted treatments. Moreover, combination drug therapies might overcome the emergence of drug resistance. Here, we performed a focused flow-cytometry-based drug synergy screen and identified a novel synergistic interaction between GLUT1-mediated glucose transport and the cell cycle checkpoint kinases ATR and CHK1. Combined inhibition of CHK1/GLUT1 or ATR/GLUT1 robustly induced apoptosis, particularly in RAS-mutant cancer cells. Mechanistically, combined inhibition of ATR/CHK1 and GLUT1 arrested sensitive cells in S-phase and led to the accumulation of genotoxic damage, particularly in S-phase. In vivo, simultaneous inhibition of ATR and GLUT1 significantly reduced tumor volume gain in an autochthonous mouse model of KrasG12D-driven soft tissue sarcoma. Taken together, these findings pave the way for combined inhibition of GLUT1 and ATR/CHK1 as a therapeutic approach for KRAS-driven cancers.

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