ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status
Open Access
- 3 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 10 (1), 1-8
- https://doi.org/10.1038/s41598-020-63294-z
Abstract
Only few drugs have shown activity in patients with advanced soft-tissue and the median overall survival is only 18 months. Alterations of genes involved in the DNA damage repair pathway have been associated with sarcoma risk and prognosis. ATR plays a crucial role in maintaining genomic integrity by responding to a large spectrum of DNA damage, including double strand breaks (DSBs) that interfere with replication. The objective of this study is to evaluate the pre-clinical activity of ATR inhibition in soft tissue sarcomas (STS). We explored the ability of the ATR inhibitor, VE-822, to prevent chemotherapy-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo in STS cell lines and in a patient-derived xenograft model. The combination of VE-822 and gemcitabine in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the S phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced gamma H2AX intranuclear accumulation as a result of DNA damage induction. These effects were unrelated to the alternative lengthening of telomeres pathway. In vivo, the combination of VE-822 and gemcitabine significantly enhanced tumor growth inhibition and progression-free survival in an aggressive model of undifferentiated pleomorphic sarcoma. The combination of ATR inhibitor and chemotherapy is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.Funding Information
- Institut National Du Cancer (INCA DGOS INSERM 6046)
This publication has 24 references indexed in Scilit:
- Unravelling mechanisms of p53-mediated tumour suppressionNature Reviews Cancer, 2014
- Targeting ATR in DNA damage response and cancer therapeuticsCancer Treatment Reviews, 2013
- Prevalence of the Alternative Lengthening of Telomeres Telomere Maintenance Mechanism in Human Cancer SubtypesThe American Journal of Pathology, 2011
- Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATRNature Chemical Biology, 2011
- ATR mediates cisplatin resistance in a p53 genotype-specific mannerOncogene, 2011
- Constant p53 Pathway Inactivation in a Large Series of Soft Tissue Sarcomas with Complex GeneticsThe American Journal of Pathology, 2010
- Trends in survival for patients with metastatic soft‐tissue sarcomaCancer, 2010
- Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexityNature Medicine, 2010
- ATR inhibition selectively sensitizes G 1 checkpoint-deficient cells to lethal premature chromatin condensationProceedings of the National Academy of Sciences of the United States of America, 2001
- Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitorsAdvances in Enzyme Regulation, 1984