Ludwig Center for Metastasis Research and Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
Cell Chem Biol. 2022 Oct 20;29(10):1517-1531.e7. doi: 10.1016/j.chembiol.2022.09.002. Epub 2022 Oct 6.
Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.
除了合成端粒重复序列外，端粒酶逆转录酶（TERT）还具有多种其他功能，支持癌症生长。阻断端粒酶以驱动端粒磨损似乎不太可行，但 TERT 的非规范活性尚未作为癌症靶点得到充分探索。在这里，我们使用一种不可逆的 TERT 抑制剂 NU-1 来研究其对常规癌症治疗耐药性的影响。在体外，抑制 TERT 可使细胞对化疗和放疗敏感。NU-1 延迟了双链断裂的修复，导致持续的 DNA 损伤信号和细胞衰老。虽然 NU-1 单独使用不会影响 BALB/c 小鼠中同基因 CT26 肿瘤的生长，但它可显著增强放疗的效果，导致免疫依赖性肿瘤消除。肿瘤显示持续的 DNA 损伤、抑制增殖和增加激活的免疫浸润。我们的研究证实了 TERT 在限制常规治疗的遗传毒性作用中的作用，但也表明 TERT 是免疫逃避和治疗耐药性的决定因素。
