Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization

• Published in: Cell chemical biology Vol. 29; no. 10; p. 1517
• Main Authors: Liu, Yue, Betori, Rick C, Pagacz, Joanna, Frost, Grant B, Efimova, Elena V, Wu, Ding, Wolfgeher, Donald J, Bryan, Tracy M, Cohen, Scott B, Scheidt, Karl A, Kron, Stephen J
• Format: Journal Article
• Language: English
• Published: United States 20-10-2022
• Subjects: Animals; Cellular Senescence - drug effects; DNA Damage - drug effects; Mice; Radiation Tolerance - drug effects; Telomerase - antagonists & inhibitors; Telomerase - metabolism; Telomere; senescence; combination therapy; TERT; anti-tumor immunity; DNA damage response; radiation
• DOI: 10.1016/j.chembiol.2022.09.002
• EISSN: 2451-9448

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.