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Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors

Goncalves, T; Zoumpoulidou, G; Alvarez-Mendoza, C; Mancusi, C; Collopy, LC; Strauss, SJ; Mittnacht, S; (2020) Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors. ACS Pharmacology & Translational Science , 3 (6) pp. 1253-1264. 10.1021/acsptsci.0c00125. Green open access

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Abstract

To avoid replicative senescence or telomere-induced apoptosis, cancers employ telomere maintenance mechanisms (TMMs) involving either the upregulation of telomerase or the acquisition of recombination-based alternative telomere lengthening (ALT). The choice of TMM may differentially influence cancer evolution and be exploitable in targeted therapies. Here, we examine TMMs in a panel of 17 osteosarcoma-derived cell lines, defining three separate groups according to TMM and the length of telomeres maintained. Eight were ALT-positive, including the previously uncharacterized lines, KPD and LM7. While ALT-positive lines all showed excessive telomere length, ALT-negative cell lines fell into two groups according to their telomere length: HOS-MNNG, OHSN, SJSA-1, HAL, 143b, and HOS displayed subnormally short telomere length, while MG-63, MHM, and HuO-3N1 displayed long telomeres. Hence, we further subcategorized ALT-negative TMM into long-telomere (LT) and short-telomere (ST) maintenance groups. Importantly, subnormally short telomeres were significantly associated with hypersensitivity to three different therapeutics targeting the protein kinase ataxia telangiectasia and Rad3-related (ATR) (AZD-6738/Ceralasertib, VE-822/Berzoserib, and BAY-1895344) compared to long telomeres maintained via ALT or telomerase. Within 24 h of ATR inhibition, cells with short but not long telomeres displayed chromosome bridges and underwent cell death, indicating a selective dependency on ATR for chromosome stability. Collectively, our work provides a resource to identify links between the mode of telomere maintenance and drug sensitivity in osteosarcoma and indicates that telomere length predicts ATR inhibitor sensitivity in cancer.

Type: Article
Title: Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acsptsci.0c00125
Publisher version: https://doi.org/10.1021/acsptsci.0c00125
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Short telomere; telomerase; alternative lengthening of telomeres; osteosarcoma; ATR inhibitors; chromosome bridge
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10113268
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