Universität zu Köln

Erber, Johanna ORCID: 0000-0001-6614-6051, Steiner, Joachim D., Isensee, Joerg ORCID: 0000-0002-3390-0051, Lobbes, Leonard A., Toschka, Andre, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Schmitt, Anna, Kaiser, Rainer W. J., Siedek, Florian, Persigehl, Thorsten, Hucho, Tim and Reinhardt, Hans C. (2019). Dual Inhibition of GLUT1 and the ATR/CHK1 Kinase Axis Displays Synergistic Cytotoxicity in KRAS-Mutant Cancer Cells. Cancer Res., 79 (19). S. 4855 - 4869. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

The advent of molecularly targeted therapeutic agents has opened a new era in cancer therapy. However, many tumors rely on nondruggable 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. Significance: Dual targeting of the DNA damage response and glucose transport synergistically induces apoptosis in KRAS-mutant cancer, suggesting this combination treatment for clinical validation in KRAS-stratified tumor patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Erber, Johanna UNSPECIFIED orcid.org/0000-0001-6614-6051 UNSPECIFIED Steiner, Joachim D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Isensee, Joerg UNSPECIFIED orcid.org/0000-0002-3390-0051 UNSPECIFIED Lobbes, Leonard A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toschka, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Schmitt, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaiser, Rainer W. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Siedek, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Persigehl, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Hucho, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-132598
DOI:	10.1158/0008-5472.CAN-18-3959
Journal or Publication Title:	Cancer Res.
Volume:	79
Number:	19
Page Range:	S. 4855 - 4869
Date:	2019
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE; RAS ONCOGENES; CHK1; WEE1; MUTATIONS; CRIZOTINIB; ACCUMULATION; SENSITIVITY; SENESCENCE; THERAPIES Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13259