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

[Image: see text] 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 differentiall...

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Autores principales: Goncalves, Tomas, Zoumpoulidou, Georgia, Alvarez-Mendoza, Carlos, Mancusi, Caterina, Collopy, Laura C., Strauss, Sandra J., Mittnacht, Sibylle, Tomita, Kazunori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737214/
https://www.ncbi.nlm.nih.gov/pubmed/33344901
http://dx.doi.org/10.1021/acsptsci.0c00125
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author Goncalves, Tomas
Zoumpoulidou, Georgia
Alvarez-Mendoza, Carlos
Mancusi, Caterina
Collopy, Laura C.
Strauss, Sandra J.
Mittnacht, Sibylle
Tomita, Kazunori
author_facet Goncalves, Tomas
Zoumpoulidou, Georgia
Alvarez-Mendoza, Carlos
Mancusi, Caterina
Collopy, Laura C.
Strauss, Sandra J.
Mittnacht, Sibylle
Tomita, Kazunori
author_sort Goncalves, Tomas
collection PubMed
description [Image: see text] 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.
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spelling pubmed-77372142021-10-07 Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors Goncalves, Tomas Zoumpoulidou, Georgia Alvarez-Mendoza, Carlos Mancusi, Caterina Collopy, Laura C. Strauss, Sandra J. Mittnacht, Sibylle Tomita, Kazunori ACS Pharmacol Transl Sci [Image: see text] 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. American Chemical Society 2020-10-07 /pmc/articles/PMC7737214/ /pubmed/33344901 http://dx.doi.org/10.1021/acsptsci.0c00125 Text en © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Goncalves, Tomas
Zoumpoulidou, Georgia
Alvarez-Mendoza, Carlos
Mancusi, Caterina
Collopy, Laura C.
Strauss, Sandra J.
Mittnacht, Sibylle
Tomita, Kazunori
Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
title Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
title_full Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
title_fullStr Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
title_full_unstemmed Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
title_short Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
title_sort selective elimination of osteosarcoma cell lines with short telomeres by ataxia telangiectasia and rad3-related inhibitors
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737214/
https://www.ncbi.nlm.nih.gov/pubmed/33344901
http://dx.doi.org/10.1021/acsptsci.0c00125
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