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mTORC1/2 and Protein Translation Regulate Levels of CHK1 and the Sensitivity to CHK1 Inhibitors in Ewing Sarcoma Cells.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2018 Dec; Vol. 17 (12), pp. 2676-2688. Date of Electronic Publication: 2018 Oct 03. - Publication Year :
- 2018
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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.<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation drug effects
Deoxycytidine analogs & derivatives
Deoxycytidine pharmacology
Drug Synergism
Humans
Phosphoproteins metabolism
Phosphorylation drug effects
Pyrazines pharmacology
Pyrazoles pharmacology
Xenograft Model Antitumor Assays
Gemcitabine
Checkpoint Kinase 1 metabolism
Mechanistic Target of Rapamycin Complex 1 metabolism
Mechanistic Target of Rapamycin Complex 2 metabolism
Protein Biosynthesis drug effects
Protein Kinase Inhibitors pharmacology
Sarcoma, Ewing enzymology
Sarcoma, Ewing pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 17
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 30282812
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-18-0260