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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.

Author information

1
Department I of Internal Medicine, University Hospital Cologne hanna.erber@gmail.com.
2
Department I of Internal Medicine, University Hospital Cologne.
3
Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital of Cologne.
4
Department of General, Visceral and Vascular surgery, Charité Universitätsmedizin Berlin.
5
Department II of Internal Medicine, University Hospital Cologne.
6
Institute of Diagnostic and Interventional Radiology, University Hospital Cologne.
7
Department of Radiology, University Hospital Cologne.
8
Department of Anesthesiology and Intensive Care Medicine, Translational Pain Research.

Abstract

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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