ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status

• Published in: Scientific reports Vol. 10; no. 1; p. 7488
• Main Authors: Laroche-Clary, Audrey, Chaire, Vanessa, Verbeke, Stéphanie, Algéo, Marie-Paule, Malykh, Andrei, Le Loarer, François, Italiano, Antoine
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.05.2020; Nature Publishing Group UK
• Subjects: Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - metabolism; Cancer; Cell cycle; Cell Line, Tumor; Cell proliferation; Chemotherapy; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; Female; Gemcitabine; Growth inhibition; Humans; Isoxazoles - pharmacology; Life Sciences; Medical prognosis; Mice; Mice, Knockout; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Pharmaceutical sciences; Pharmacology; Pyrazines - pharmacology; S phase; S Phase Cell Cycle Checkpoints - drug effects; Sarcoma; Sarcoma - drug therapy; Sarcoma - metabolism; Sarcoma - pathology; Telomere Homeostasis - drug effects; Telomeres; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-63294-z

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.