Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
To prevent replicative senescence or telomere-caused apoptosis, cancers employ telomere maintenance mechanisms (TMMs) involving either the upregulation of telomerase or even the purchase of recombination-based alternative telomere lengthening (ALT). The option of TMM may differentially influence cancer evolution and become exploitable in targeted therapies. Here, we examine TMMs inside a panel of 17 osteosarcoma-derived cell lines, defining three separate groups based on TMM and the size of telomeres maintained. Eight were ALT-positive, such as the formerly uncharacterized lines, KPD and LM7. While ALT-positive lines all demonstrated excessive telomere length, ALT-negative cell lines fell into two groups based on 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 lengthy telomeres. Hence, we further subcategorized ALT-negative TMM into lengthy-telomere (LT) and short-telomere (ST) maintenance groups. Importantly, subnormally short telomeres were considerably connected with hypersensitivity to 3 different therapeutics individuals protein kinase ataxia telangiectasia and Rad3-related (ATR) (AZD-6738/Ceralasertib, VE-822/Berzoserib, and BAY-1895344) when compared with lengthy telomeres maintained via ALT or telomerase. Within 24 h of ATR inhibition, cells with short although not lengthy telomeres displayed chromosome bridges and went through cell dying, indicating a selective reliance upon ATR for chromosome stability. With each other, our work supplies a resource to recognize links between your mode of telomere maintenance and drug sensitivity in osteosarcoma and signifies that telomere length predicts ATR inhibitor sensitivity in cancer.