Targeting Telomerase Reverse Transcriptase with the Covalent Inhibitor NU-1 Confers Immunogenic Radiation Sensitization

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2022 Oct 7

PMID 36206753

Authors

Yue Liu

Rick C Betori

Joanna Pagacz

Grant B Frost

Elena V Efimova

Ding Wu

Donald J Wolfgeher

Tracy M Bryan

Scott B Cohen

Karl A Scheidt

Stephen J Kron

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Canonical and non-canonical functions of the non-coding RNA component (TERC) of telomerase complex.

Cao C, Gong W, Shuai Y, Rasouli S, Ge Q, Khan A Cell Biosci. 2025; 15(1):30.

PMID: 40025596 PMC: 11871756. DOI: 10.1186/s13578-025-01367-0.

Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics.

Shou S, Maolan A, Zhang D, Jiang X, Liu F, Li Y Exp Hematol Oncol. 2025; 14(1):8.

PMID: 39871386 PMC: 11771031. DOI: 10.1186/s40164-025-00597-9.

Genomic profiling and molecular characterization of non-clear cell renal cell carcinoma: a narrative review from a clinical perspective.

Pezzicoli G, Musci V, Ciciriello F, Salonne F, Cafforio P, Lionetti N Ther Adv Med Oncol. 2024; 16:17588359241298500.

PMID: 39563719 PMC: 11574901. DOI: 10.1177/17588359241298500.

Kaempferol Synergistically Enhances Cisplatin-induced Apoptosis and Cell Cycle Arrest in Colon Cancer Cells.

Haroon M, Kang S J Cancer Prev. 2024; 29(3):69-87.

PMID: 39398110 PMC: 11467758. DOI: 10.15430/JCP.24.013.

Unveiling the Molecular Features of SCLC With a Clinical RNA Expression Panel.

Ozakinci H, Alontaga A, Cano P, Koomen J, Perez B, Beg A JTO Clin Res Rep. 2024; 5(11):100723.

PMID: 39386315 PMC: 11459576. DOI: 10.1016/j.jtocrr.2024.100723.

References

Meng Y, Efimova E, Hamzeh K, Darga T, Mauceri H, Fu Y . Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine. Mol Ther. 2012; 20(5):1046-55. PMC: 3345982. DOI: 10.1038/mt.2012.19. View

Singhapol C, Pal D, Czapiewski R, Porika M, Nelson G, Saretzki G . Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PLoS One. 2013; 8(1):e52989. PMC: 3541395. DOI: 10.1371/journal.pone.0052989. View

Kramer A, Green J, Pollard Jr J, Tugendreich S . Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2013; 30(4):523-30. PMC: 3928520. DOI: 10.1093/bioinformatics/btt703. View

Mender I, Zhang A, Ren Z, Han C, Deng Y, Siteni S . Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity. Cancer Cell. 2020; 38(3):400-411.e6. PMC: 7494563. DOI: 10.1016/j.ccell.2020.05.020. View

Massard C, Zermati Y, Pauleau A, Larochette N, Metivier D, Sabatier L . hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene. 2006; 25(33):4505-14. DOI: 10.1038/sj.onc.1209487. View

Ahmed S, Passos J, Birket M, Beckmann T, Brings S, Peters H . Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci. 2008; 121(Pt 7):1046-53. DOI: 10.1242/jcs.019372. View

Chabanon R, Rouanne M, Lord C, Soria J, Pasero P, Postel-Vinay S . Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat Rev Cancer. 2021; 21(11):701-717. DOI: 10.1038/s41568-021-00386-6. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

Mao Z, Bozzella M, Seluanov A, Gorbunova V . DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle. 2008; 7(18):2902-6. PMC: 2754209. DOI: 10.4161/cc.7.18.6679. View

10.

Shin K, Kang M, Dicterow E, Kameta A, Baluda M, Park N . Introduction of human telomerase reverse transcriptase to normal human fibroblasts enhances DNA repair capacity. Clin Cancer Res. 2004; 10(7):2551-60. DOI: 10.1158/1078-0432.ccr-0669-3. View

11.

Herbert B, Gellert G, Hochreiter A, Pongracz K, Wright W, Zielinska D . Lipid modification of GRN163, an N3'-->P5' thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition. Oncogene. 2005; 24(33):5262-8. DOI: 10.1038/sj.onc.1208760. View

12.

Ghanim G, Fountain A, van Roon A, Rangan R, Das R, Collins K . Structure of human telomerase holoenzyme with bound telomeric DNA. Nature. 2021; 593(7859):449-453. PMC: 7610991. DOI: 10.1038/s41586-021-03415-4. View

13.

Wong K, Chang S, Weiler S, Ganesan S, Chaudhuri J, Zhu C . Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet. 2000; 26(1):85-8. DOI: 10.1038/79232. View

14.

Sutherland R, Hall R, TAYLOR I . Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res. 1983; 43(9):3998-4006. View

15.

Berardinelli F, Coluzzi E, Sgura A, Antoccia A . Targeting telomerase and telomeres to enhance ionizing radiation effects in in vitro and in vivo cancer models. Mutat Res Rev Mutat Res. 2017; 773:204-219. DOI: 10.1016/j.mrrev.2017.02.004. View

16.

Segal-Bendirdjian E, Geli V . Non-canonical Roles of Telomerase: Unraveling the Imbroglio. Front Cell Dev Biol. 2020; 7:332. PMC: 6914764. DOI: 10.3389/fcell.2019.00332. View

17.

Thompson C, Wong J . Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance. Curr Top Med Chem. 2020; 20(6):498-507. DOI: 10.2174/1568026620666200131125110. View

18.

Fleisig H, Hukezalie K, Thompson C, Au-Yeung T, Ludlow A, Zhao C . Telomerase reverse transcriptase expression protects transformed human cells against DNA-damaging agents, and increases tolerance to chromosomal instability. Oncogene. 2015; 35(2):218-27. DOI: 10.1038/onc.2015.75. View

19.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

20.

Wang Y, Sun C, Mao A, Zhang X, Zhou X, Wang Z . Radiosensitization to X-ray radiation by telomerase inhibitor MST-312 in human hepatoma HepG2 cells. Life Sci. 2015; 123:43-50. DOI: 10.1016/j.lfs.2014.12.027. View