Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors,ACS Pharmacology & Translational Science

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Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by Ataxia Telangiectasia and Rad3-Related Inhibitors
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-10-07 , DOI: 10.1021/acsptsci.0c00125
Tomas Goncalves _{1,

2} , Georgia Zoumpoulidou ₃ , Carlos Alvarez-Mendoza ₃ , Caterina Mancusi ₃ , Laura C Collopy ₂ , Sandra J Strauss _{4,

5} , Sibylle Mittnacht ₃ , Kazunori Tomita _{1,

2}

Affiliation

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.

中文翻译：

通过共济失调毛细血管扩张症和 Rad3 相关抑制剂选择性消除具有短端粒的骨肉瘤细胞系

为了避免复制衰老或端粒诱导的细胞凋亡，癌症采用端粒维持机制 (TMM)，包括端粒酶的上调或获得基于重组的替代端粒延长 (ALT)。TMM 的选择可能对癌症进化产生不同的影响，并可用于靶向治疗。在这里，我们检查了一组 17 个骨肉瘤衍生细胞系中的 TMM，根据 TMM 和维持的端粒长度定义了三个独立的组。八种是 ALT 阳性，包括以前未表征的品系、KPD 和 LM7。虽然 ALT 阳性细胞系都表现出过长的端粒长度，但 ALT 阴性细胞系根据它们的端粒长度分为两组：HOS-MNNG、OHSN、SJSA-1、HAL、143b 和 HOS 显示出低于正常的端粒长度，而 MG -63，MHM，和 HuO-3N1 显示长端粒。因此，我们进一步将 ALT 阴性 TMM 细分为长端粒 (LT) 和短端粒 (ST) 维持组。重要的是，与维持长端粒相比，亚正常短端粒与针对蛋白激酶共济失调毛细血管扩张症和 Rad3 相关 (ATR)（AZD-6738/Ceralasertib、VE-822/Berzoserib 和 BAY-1895344）的三种不同疗法的超敏反应显着相关通过 ALT 或端粒酶。在 ATR 抑制的 24 小时内，端粒短但不长的细胞显示染色体桥并经历细胞死亡，表明染色体稳定性选择性依赖于 ATR。总的来说，

更新日期：2020-12-12

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