Goncalves Tomas, Zoumpoulidou Georgia, Alvarez-Mendoza Carlos, Mancusi Caterina, Collopy Laura C, Strauss Sandra J, Mittnacht Sibylle, Tomita Kazunori
Centre for Genome Engineering and Maintenance, College of Health, Medicine and Life Sciences, Brunel University London, London UB8 3PH, United Kingdom.
Chromosome Maintenance Group, UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom.
ACS Pharmacol Transl Sci. 2020 Oct 7;3(6):1253-1264. doi: 10.1021/acsptsci.0c00125. eCollection 2020 Dec 11.
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.
为避免复制性衰老或端粒诱导的细胞凋亡，癌症会采用端粒维持机制（TMMs），包括上调端粒酶或获得基于重组的替代性端粒延长（ALT）。TMM的选择可能对癌症进化产生不同影响，并且在靶向治疗中具有可利用性。在此，我们检测了一组17种骨肉瘤来源的细胞系中的TMMs，根据TMM和维持的端粒长度定义了三个不同的组。八个是ALT阳性，包括之前未表征的细胞系KPD和LM7。虽然ALT阳性细胞系均显示端粒长度过长，但ALT阴性细胞系根据其端粒长度分为两组：HOS-MNNG、OHSN、SJSA-1、HAL、143b和HOS显示端粒长度异常短，而MG-63、MHM和HuO-3N1显示端粒长。因此，我们将ALT阴性TMM进一步细分为长端粒（LT）和短端粒（ST）维持组。重要的是，与通过ALT或端粒酶维持的长端粒相比，异常短的端粒与对三种靶向蛋白激酶共济失调毛细血管扩张症和Rad3相关蛋白（ATR）的不同治疗药物（AZD-6738/西拉司他、VE-822/贝佐司他和BAY-1895344）的超敏反应显著相关。在抑制ATR的24小时内，具有短端粒而非长端粒的细胞显示出染色体桥并发生细胞死亡，表明在染色体稳定性方面对ATR存在选择性依赖。总体而言，我们的工作提供了一种资源，以确定骨肉瘤中端粒维持模式与药物敏感性之间的联系，并表明端粒长度可预测癌症中ATR抑制剂的敏感性。
