Journal article
mTORC1/2 and Protein Translation Regulate Levels of CHK1 and the Sensitivity to CHK1 Inhibitors in Ewing Sarcoma Cells
Molecular cancer therapeutics, Vol.17(12), pp.2676-2688
12/01/2018
DOI: 10.1158/1535-7163.MCT-18-0260
PMCID: PMC6279492
PMID: 30282812
Abstract
The treatment of Ewing sarcoma has changed very little in the past two decades and novel treatment approaches are needed. We recently identified that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides. We subsequently found that the inhibition of checkpoint kinase 1 (CHK1) increases the sensitivity of Ewing sarcoma cells to inhibitors of RNR, such as gemcitabine. However, Ewing sarcoma cells exhibit high levels of the CHK1 protein, which may represent an adaptive response to elevated levels of endogenous DNA replication stress. Consequently, we began this work with the aim of determining the impact of CHK1 levels on drug sensitivity, as well as identifying the mechanisms and pathways that regulate CHK1 levels in Ewing sarcoma cells. In this report, we show that the high levels of the CHK1 protein in Ewing sarcoma cells limit the efficacy of CHK1 inhibitors. However, inhibition of mTORC1/2 activates the translational repressor 4E-BP1, reduces protein synthesis, and decreases levels of the CHK1 protein in Ewing sarcoma cells. Similarly, we identified that the CHK1 inhibitor prexasertib also activates 4E-BP1, inhibits protein synthesis, and reduces CHK1 protein levels in Ewing sarcoma cells. Moreover, the combination of prexasertib and gemcitabine was synergistic in vitro, caused tumor regression in vivo, and significantly prolonged mouse survival in a Ewing sarcoma xenograft experiment. Overall, our results provide insight into Ewing sarcoma biology and support further investigation of the CHK1 pathway as a therapeutic target in Ewing sarcoma tumors. (C) 2018 AACR.
Details
- Title: Subtitle
- mTORC1/2 and Protein Translation Regulate Levels of CHK1 and the Sensitivity to CHK1 Inhibitors in Ewing Sarcoma Cells
- Creators
- Stacia L. Koppenhafer - University of IowaKelli L. Goss - University of IowaWilliam W. Terry - University of IowaDavid J. Gordon - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.17(12), pp.2676-2688
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1535-7163.MCT-18-0260
- PMID
- 30282812
- PMCID
- PMC6279492
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Number of pages
- 13
- Grant note
- University of Iowa Dance Marathon Award Matt Morrell and Natalie Sanchez Pediatric Cancer Research Foundation R37CA217910 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) University of Iowa Oberley Seed Grant University of Iowa Stead Family Research Award Holden Comprehensive Cancer Center Sarcoma Multidisciplinary Oncology Group Seed Grant R37-CA217910 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 12/01/2018
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984353831402771
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