ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status
| Autor: | Stéphanie Verbeke, Audrey Laroche-Clary, François Le Loarer, Marie-Paule Algeo, Andrei Malykh, Antoine Italiano, Vanessa Chaire |
|---|---|
| Přispěvatelé: | Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Sarcoma Unit [Bordeaux], Institut Bergonié [Bordeaux], Université de Bordeaux (UB), Capital Biosciences [Rockville, MD, États-Unis], All authors were supported by Grant INCa-DGOS-Inserm 6046., Bodescot, Myriam |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer therapy
DNA damage lcsh:Medicine [SDV.CAN]Life Sciences [q-bio]/Cancer Ataxia Telangiectasia Mutated Proteins Article Undifferentiated Pleomorphic Sarcoma Mice [SDV.CAN] Life Sciences [q-bio]/Cancer In vivo Cell Line Tumor Animals Humans Medicine lcsh:Science S phase Mice Knockout Multidisciplinary business.industry Cell growth Soft tissue sarcoma lcsh:R Telomere Homeostasis Sarcoma Isoxazoles medicine.disease Xenograft Model Antitumor Assays Neoplasm Proteins Apoptosis Pyrazines [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology S Phase Cell Cycle Checkpoints Cancer research [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology Female lcsh:Q business DNA Damage |
| Zdroj: | Scientific Reports Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.7488. ⟨10.1038/s41598-020-63294-z⟩ Scientific Reports, Vol 10, Iss 1, Pp 1-8 (2020) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-63294-z⟩ |
| Popis: | 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 γH2AX 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. |
| Databáze: | OpenAIRE |
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