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Targeting telomerase for cancer therapy

Abstract

Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. In contrast, telomerase activity is silenced in most adult somatic cells. Thus, telomerase represents an attractive target for highly selective cancer therapeutics. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. The discovery of prevalent mutations in the TERT promoter region in many cancers and recent advances in telomerase biology has led to a renewed interest in targeting this enzyme. Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches such as targeting TERT gene expression driven by TERT promoter mutations. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase.

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Fig. 1: Therapeutic strategies for targeting telomerase.
Fig. 2: TERT promoter regulation: a new therapeutic avenue in cancer?.

References

  1. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–5.

    CAS  PubMed  Google Scholar 

  2. Morrison SJ, Prowse KR, Ho P, Weissman IL. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity. 1996;5:207–16.

    CAS  PubMed  Google Scholar 

  3. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100–10.

    PubMed  Google Scholar 

  4. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. Mammalian telomeres end in a large duplex loop. Cell. 1999;97:503–14.

    CAS  PubMed  Google Scholar 

  5. Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol. 1992;225:951–60.

    CAS  PubMed  Google Scholar 

  6. Hackett JA, Greider CW. End resection initiates genomic instability in the absence of telomerase. Mol Cell Biol. 2003;23:8450–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43:405–13.

    CAS  PubMed  Google Scholar 

  8. Schmidt JC, Cech TR. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 2015;29:1095–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279:349–52.

    CAS  PubMed  Google Scholar 

  10. Baena-Del Valle JA, Zheng Q, Esopi DM, Rubenstein M, Hubbard GK, Moncaliano MC, et al. MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. J Pathol. 2018;244:11–24.

    CAS  PubMed  Google Scholar 

  11. Cao Y, Bryan TM, Reddel RR. Increased copy number of the TERT and TERC telomerase subunit genes in cancer cells. Cancer Sci. 2008;99:1092–9.

    CAS  PubMed  Google Scholar 

  12. Jacobs JJL, de Lange T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol. 2004;14:2302–8.

    CAS  PubMed  Google Scholar 

  13. Chiba K, Lorbeer FK, Shain AH, McSwiggen DT, Schruf E, Oh A, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science. 2017;357:1416–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Barthel FP, Wei W, Tang M, Martinez-Ledesma E, Hu X, Amin SB, et al. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat Genet. 2017;49:349–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ouellette MM, Liao M, Herbert BS, Johnson M, Holt SE, Liss HS, et al. Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase. J Biol Chem. 2000;275:10072–6.

    CAS  PubMed  Google Scholar 

  16. Vinagre J, Almeida A, Pópulo H, Batista R, Lyra J, Pinto V, et al. Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013;4:959–6.

    Google Scholar 

  17. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339:957–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bell RJA, Rube HT, Kreig A, Mancini A, Fouse SD, Nagarajan RP, et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015;348:1036–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Stern JL, Theodorescu D, Vogelstein B, Papadopoulos N, Cech TR. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 2015;29:2219–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet. 2014;46:1160–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545:175–80.

    CAS  PubMed  Google Scholar 

  22. Labussière M, Boisselier B, Mokhtari K, Di Stefano A-L, Rahimian A, Rossetto M, et al. Combined analysis of TERT, EGFR, and IDH status defines distinct prognostic glioblastoma classes. Neurology. 2014;83:1200–6.

    PubMed  Google Scholar 

  23. Griewank KG, Murali R, Puig-Butille JA, Schilling B, Livingstone E, Potrony M, et al. TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Inst. 2014;106:949.

    Google Scholar 

  24. Spiegl-Kreinecker S, Lötsch D, Neumayer K, Kastler L, Gojo J, Pirker C, et al. TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma. Neuro-Oncol. 2018;20:1584–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sahm F, Schrimpf D, Olar A, Koelsche C, Reuss D, Bissel J, et al. TERT promoter mutations and risk of recurrence in meningioma. J. Natl Cancer Inst. 2016;108:djv377.

    Google Scholar 

  26. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA. 2013;110:6021–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee DD, Leão R, Komosa M, Gallo M, Zhang CH, Lipman T, et al. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer. J Clin Invest. 2019;129:223–9.

    PubMed  Google Scholar 

  28. Kim W, Ludlow AT, Min J, Robin JD, Stadler G, Mender I, et al. Regulation of the human telomerase gene TERT by telomere position effect-over long distances (TPE-OLD): implications for aging and cancer. PLoS Biol. 2016;14:e2000016.

    PubMed  PubMed Central  Google Scholar 

  29. Zhu X, Han W, Xue W, Zou Y, Xie C, Du J, et al. The association between telomere length and cancer risk in population studies. Sci Rep. 2016;6:518.

    Google Scholar 

  30. Telomeres Mendelian Randomization Collaboration, Haycock PC, Burgess S, Nounu A, Zheng J, Okoli GN, et al. Association between telomere length and risk of cancer and non-neoplastic diseases: a mendelian randomization study. JAMA Oncol. 2017;3:636–51.

    Google Scholar 

  31. Zhang C, Doherty JA, Burgess S, Hung RJ, Lindström S, Kraft P, et al. Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Hum Mol Genet. 2015;24:5356–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Aviv A, Anderson JJ, Shay JW. Mutations, cancer and the telomere length paradox. Trends Cancer. 2017;3:253–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107:67–77.

    CAS  PubMed  Google Scholar 

  34. Lai T-P, Zhang N, Noh J, Mender I, Tedone E, Huang E, et al. A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat Commun. 2017;8:1356.

    PubMed  PubMed Central  Google Scholar 

  35. Chiappori AA, Kolevska T, Spigel DR, Hager S, Rarick M, Gadgeel S, et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol. 2015;26:354–62.

    CAS  PubMed  Google Scholar 

  36. Notaro R, Cimmino A, Tabarini D, Rotoli B, Luzzatto L. In vivo telomere dynamics of human hematopoietic stem cells. Proc Natl Acad Sci. 1997;94:13782–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Masutomi K, Possemato R, Wong JMY, Currier JL, Tothova Z, Manola JB, et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc Natl Acad Sci USA. 2005;102:8222–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nitta E, Yamashita M, Hosokawa K, Xian M, Takubo K, Arai F, et al. Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism. Blood. 2011;117:4169–80.

    CAS  PubMed  Google Scholar 

  39. Koh CM, Khattar E, Leow SC, Liu CY, Muller J, Ang WX, et al. Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J Clin Invest. 2015;125:2109–22.

    PubMed  PubMed Central  Google Scholar 

  40. Perera ON, Sobinoff AP, Teber ET, Harman A, Maritz MF, Yang SF, et al. Telomerase promotes formation of a telomere protective complex in cancer cells. Sci Adv. 2019;5:eaav4409.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. El-Daly H, Kull M, Zimmermann S, Pantic M, Waller CF, Martens UM. Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532. Blood. 2005;105:1742–9.

    CAS  PubMed  Google Scholar 

  42. Hemann MT, Greider CW. Wild-derived inbred mouse strains have short telomeres. Nucleic Acids Res. 2000;28:4474–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Greenberg RA, Allsopp RC, Chin L, Morin GB, DePinho RA. Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene. 1998;16:1723–30.

    CAS  PubMed  Google Scholar 

  44. Peto R. Epidemiology, multistage models, and short-term mutagenicity tests. Int J Epidemiol. 2016;45:621–37.

    PubMed  Google Scholar 

  45. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997;91:25–34.

    CAS  PubMed  Google Scholar 

  46. Raval A, Behbehani GK, Nguyen LXT, Thomas D, Kusler B, Garbuzov A, et al. Reversibility of defective hematopoiesis caused by telomere shortening in telomerase knockout mice. PLoS ONE. 2015;10:e0131722.

    PubMed  PubMed Central  Google Scholar 

  47. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl J Med. 2005;352:1413–24.

    CAS  PubMed  Google Scholar 

  48. Sauerwald A, Sandin S, Cristofari G, Scheres SHW, Lingner J, Rhodes D. Structure of active dimeric human telomerase. Nat Struct Mol Biol. 2013;20:454–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gillis AJ, Schuller AP, Skordalakes E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 2008;455:633–7.

    CAS  PubMed  Google Scholar 

  50. Jiang J, Wang Y, Sušac L, Chan H, Basu R, Zhou ZH, et al. Structure of telomerase with telomeric DNA. Cell. 2018;173:1179–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature. 2018;557:190–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM, Veenstra TD, et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science. 2009;323:644–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Heaphy CM, Subhawong AP, Hong S-M, Goggins MG, Montgomery EA, Gabrielson E, et al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol. 2011;179:1608–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Dilley RL, Greenberg RA. ALTernative telomere maintenance and cancer. Trends Cancer. 2015;1:145–56.

    PubMed  PubMed Central  Google Scholar 

  55. Henson JD, Hannay JA, McCarthy SW, Royds JA, Yeager TR, Robinson RA, et al. A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas. Clin Cancer Res. 2005;11:217–25.

    CAS  PubMed  Google Scholar 

  56. Ramamoorthy M, Smith S. Loss of ATRX suppresses resolution of telomere cohesion to control recombination in ALT cancer cells. Cancer Cell. 2015;28:357–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Napier CE, Huschtscha LI, Harvey A, Bower K, Noble JR, Hendrickson EA, et al. ATRX represses alternative lengthening of telomeres. Oncotarget Impact J. 2015;6:16543–58.

    Google Scholar 

  58. Mukherjee J, Johannessen T-C, Ohba S, Chow TT, Jones L, Pandita A, et al. Mutant IDH1 cooperates with ATRX loss to drive the alternative lengthening of telomere phenotype in glioma. Cancer Res. 2018;78:2966–77.

    CAS  PubMed  Google Scholar 

  59. O’Sullivan RJ, Arnoult N, Lackner DH, Oganesian L, Haggblom C, Corpet A, et al. Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1. Nat Struct Mol Biol. 2014;21:167–74.

    PubMed  PubMed Central  Google Scholar 

  60. Min J, Wright WE, Shay JW. Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands. Nucleic Acids Res. 2017;45:2615–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, et al. Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell. 2012;148:651–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Tong AS, Stern JL, Sfeir A, Kartawinata M, de Lange T, Zhu X-D, et al. ATM and ATR signaling regulate the recruitment of human telomerase to telomeres. Cell Rep. 2015;13:1633–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Vonderheide RH. Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene. 2002;21:674–9.

    CAS  PubMed  Google Scholar 

  64. Lilleby W, Gaudernack G, Brunsvig PF, Vlatkovic L, Schulz M, Mills K, et al. Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer. Cancer Immunol Immunother. 2017;66:891–901.

    CAS  PubMed  Google Scholar 

  65. Zanetti M. A second chance for telomerase reverse transcriptase in anticancer immunotherapy. Nat Rev Clin Oncol. 2017;14:115–28.

    CAS  PubMed  Google Scholar 

  66. Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014;15:829–40.

    CAS  PubMed  Google Scholar 

  67. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol Front. 2018;8:86.

    Google Scholar 

  68. Duperret EK, Wise MC, Trautz A, Villarreal DO, Ferraro B, Walters J, et al. Synergy of immune checkpoint blockade with a novel synthetic consensus DNA vaccine targeting TERT. Mol Ther. 2018;26:435–45.

    CAS  PubMed  Google Scholar 

  69. Ugel S, Scarselli E, Iezzi M, Mennuni C, Pannellini T, Calvaruso F, et al. Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes. Blood. 2010;115:1374–84.

    CAS  PubMed  Google Scholar 

  70. Sandri S, Bobisse S, Moxley K, Lamolinara A, De Sanctis F, Boschi F, et al. Feasibility of telomerase-specific adoptive T-cell therapy for B-cell chronic lymphocytic leukemia and solid malignancies. Cancer Res. 2016;76:2540–51.

    CAS  PubMed  Google Scholar 

  71. Kawashima T, Kagawa S, Kobayashi N, Shirakiya Y, Umeoka T, Teraishi F, et al. Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res. 2004;10:285–92.

    CAS  PubMed  Google Scholar 

  72. Kanaya N, Kuroda S, Morihiro T, Kakiuchi Y, Kubota T, Kakiuchi S, et al. Abstract 2744: Telomelysin-induced immunogenic cell death synergizes with anti-PD-1 antibody in non-immunogenic gastrointestinal tumors. Cancer Res. 2018;78:2744–4.

    Google Scholar 

  73. Nemunaitis J, Tong AW, Nemunaitis M, Senzer N, Phadke AP, Bedell C, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18:429–34.

    CAS  PubMed  Google Scholar 

  74. Asai A, Oshima Y, Yamamoto Y, Uochi T-A, Kusaka H, Akinaga S, et al. A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res. 2003;63:3931–9.

    CAS  PubMed  Google Scholar 

  75. Thompson PA, Drissi R, Muscal JA, Panditharatna E, Fouladi M, Ingle AM, et al. A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children’s Oncology Group Phase I Consortium Study (ADVL1112). Clin Cancer Res. 2013;19:6578–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N. Engl J Med. 2015;373:908–19.

    CAS  PubMed  Google Scholar 

  77. Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, McDevitt MA, et al. Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N. Engl J Med. 2015;373:920–8.

    CAS  PubMed  Google Scholar 

  78. Armanios M, Greider CW. Treating myeloproliferation—on target or off? N. Engl J Med. 2015;373:965–6.

    PubMed  Google Scholar 

  79. Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H, et al. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001;20:6958–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bryan C, Rice C, Hoffman H, Harkisheimer M, Sweeney M, Skordalakes E. Structural basis of telomerase inhibition by the highly specific BIBR1532. Structure. 2015;23:1934–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Baell JB. Feeling nature’s PAINS: natural products, natural product drugs, and pan assay interference compounds (PAINS). J Nat Products. 2016;79:616–28.

    CAS  Google Scholar 

  82. Biffi G, Tannahill D, McCafferty J, Balasubramanian S. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat Chem. 2013;5:182–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Drosopoulos WC, Kosiyatrakul ST, Schildkraut CL. BLM helicase facilitates telomere replication during leading strand synthesis of telomeres. J Cell Biol. 2015;210:191–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Tauchi T, Shin-ya K, Sashida G, Sumi M, Okabe S, Ohyashiki JH, et al. Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia. Oncogene. 2006;25:5719–25.

    CAS  PubMed  Google Scholar 

  85. Liu W, Zhong Y-F, Liu L-Y, Shen C-T, Zeng W, Wang F, et al. Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding. Nat Commun. 2018;9:3496.

    PubMed  PubMed Central  Google Scholar 

  86. Huppert JL, Balasubramanian S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 2005;33:2908–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Moye AL, Porter KC, Cohen SB, Phan T, Zyner KG, Sasaki N, et al. Telomeric G-quadruplexes are a substrate and site of localization for human telomerase. Nat Commun. 2015;6:7643.

    PubMed  Google Scholar 

  88. Mender I, Gryaznov S, Dikmen ZG, Wright WE, Shay JW. Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2’-deoxyguanosine. Cancer Discov. 2015;5:82–95.

    CAS  PubMed  Google Scholar 

  89. Zeng X, Hernandez-Sanchez W, Xu M, Whited TL, Baus D, Zhang J, et al. Administration of a nucleoside analog promotes cancer cell death in a telomerase-dependent manner. Cell Rep. 2018;23:3031–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Mender I, LaRanger R, Luitel K, Peyton M, Girard L, Lai T-P, et al. Telomerase-mediated strategy for overcoming non-small cell lung cancer targeted therapy and chemotherapy resistance. Neoplasia. 2018;20:826–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Sengupta S, Sobo M, Lee K, Senthil Kumar S, White AR, Mender I, et al. Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors. Mol Cancer Ther. 2018;17:1504–14.

    CAS  PubMed  Google Scholar 

  92. Zhang G, Wu LW, Mender I, Barzily-Rokni M, Hammond MR, Ope O, et al. Induction of telomere dysfunction prolongs disease control of therapy-resistant melanoma. Clin Cancer Res. 2018;24:4771–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Reyes-Uribe P, Adrianzen-Ruesta MP, Deng Z, Echevarria-Vargas I, Mender I, Saheb S, et al. Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene. 2018;37:1–4072.

    Google Scholar 

  94. Atkinson SP, Hoare SF, Glasspool RM, Keith WN. Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters. Cancer Res. 2005;65:7585–90.

    CAS  PubMed  Google Scholar 

  95. Cong YS, Bacchetti S. Histone deacetylation is involved in the transcriptional repression of hTERT in normal human cells. J Biol Chem. 2000;275:35665–8.

    CAS  PubMed  Google Scholar 

  96. Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife. 2015;4:1–20.

    Google Scholar 

  97. Shain AH, Joseph NM, Yu R, Benhamida J, Liu S, Prow T, et al. Genomic and transcriptomic analysis reveals incremental disruption of key signaling pathways during melanoma evolution. Cancer Cell. 2018;34:e4.

    Google Scholar 

  98. Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218.

    PubMed  Google Scholar 

  99. Kinde I, Munari E, Faraj SF, Hruban RH, Schoenberg M, Bivalacqua T, et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 2013;73:7162–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The genetic evolution of melanoma from precursor lesions. N. Engl J Med. 2015;373:1926–36.

    PubMed  Google Scholar 

  101. Akıncılar SC, Khattar E, Boon PLS, Unal B, Fullwood MJ, Tergaonkar V. Long-range chromatin interactions drive mutant TERT promoter activation. Cancer Discov. 2016;6:1276–91.

    PubMed  Google Scholar 

  102. Vallarelli AF, Rachakonda PS, André J, Heidenreich B, Riffaud L, Bensussan A, et al. TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation. Oncotarget Impact J. 2016;7:53127–36.

    Google Scholar 

  103. Li Y, Zhou Q-L, Sun W, Chandrasekharan P, Cheng HS, Ying Z, et al. Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat Cell Biol. 2015;17:1327–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Mancini A, Xavier-Magalhães A, Woods WS, Nguyen K-T, Amen AM, Hayes JL, et al. Disruption of the β1L isoform of GABP reverses glioblastoma replicative immortality in a TERT promoter mutation-dependent manner. Cancer Cell. 2018;34:513–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Ristevski S, O’Leary DA, Thornell AP, Owen MJ, Kola I, Hertzog PJ. The ETS transcription factor GABPalpha is essential for early embryogenesis. Mol Cell Biol. 2004;24:5844–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Xue H-H, Jing X, Bollenbacher-Reilley J, Zhao D-M, Haring JS, Yang B, et al. Targeting the GA binding protein beta1L isoform does not perturb lymphocyte development and function. Mol Cell Biol. 2008;28:4300–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Li Y, Cheng HS, Chng WJ, Tergaonkar V. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas. Proc Natl Acad Sci USA. 2016;113:14402–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Ludlow AT, Wong MS, Robin JD, Batten K, Yuan L, Lai T-P, et al. NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. Nat Commun. 2018;9:3112.

    PubMed  PubMed Central  Google Scholar 

  109. Sayed ME, Yuan L, Robin JD, Tedone E, Batten K, Dahlson N, et al. NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells. Oncogene. OncogeneNat Publ Group. 2019;38:2937–52.

    CAS  Google Scholar 

  110. Chen L, Roake CM, Freund A, Batista PJ, Tian S, Yin YA, et al. An activity switch in human telomerase based on RNA conformation and shaped by TCAB1. Cell. 2018;174:218–.e13.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Stern JL, Zyner KG, Pickett HA, Cohen SB, Bryan TM. Telomerase recruitment requires both TCAB1 and Cajal bodies independently. Mol Cell Biol. 2012;32:2384–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Sun C-K, Luo X-B, Gou Y-P, Hu L, Wang K, Li C. et al. TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas. Mol. Cancer. 2014;13:180

    PubMed  PubMed Central  Google Scholar 

  113. Bandaria JN, Qin P, Berk V, Chu S, Yildiz A. Shelterin protects chromosome ends by compacting telomeric chromatin. Cell. 2016;164:735–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, et al. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage. EMBO Mol Med. 2015;7:930–49.

    PubMed  PubMed Central  Google Scholar 

  115. Bejarano L, Bosso G, Louzame J, Serrano R, Gómez-Casero E, Martínez-Torrecuadrada J, et al. Multiple cancer pathways regulate telomere protection. EMBO Mol Med. 2019;11:e10292.

  116. McKerlie M, Lin S, Zhu X-D. ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance. Nucleic Acids Res. 2012;40:3975–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature. 2012;492:285–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Nakashima M, Nandakumar J, Sullivan KD, Espinosa JM, Cech TR. Inhibition of telomerase recruitment and cancer cell death. J Biol Chem. 2013;288:33171–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Spåhr H, Chia T, Lingford JP, Siira SJ, Cohen SB, Filipovska A, et al. Modular ssDNA binding and inhibition of telomerase activity by designer PPR proteins. Nat Commun. 2018;9:2212.

    PubMed  PubMed Central  Google Scholar 

  120. Oh S, Song YH, Yim J, Kim TK. Identification of Mad as a repressor of the human telomerase (hTERT) gene. Oncogene. 2000;19:1485–90.

    CAS  PubMed  Google Scholar 

  121. Liu R, Zhang T, Zhu G, Xing M. Regulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer. Nat Commun. 2018;9:579.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Mitchell TJ, Turajlic S, Rowan A, Nicol D, Farmery JHR, O’Brien T, et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell. 2018;173:611–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Makowski MM, Willems E, Fang J, Choi J, Zhang T, Jansen PWTC, et al. An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations. Proteomics. 2016;16:417–26.

    CAS  PubMed  Google Scholar 

  124. Yuan X, Mu N, Wang N, Strååt K, Sofiadis A, Guo Y, et al. GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression. Oncogene. 2019;38:965–79.

    CAS  PubMed  Google Scholar 

  125. Gabler L, Lötsch D, Kirchhofer D, van Schoonhoven S, Schmidt HM, Mayr L, et al. TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E/TERT promoter double-mutated glioma. Acta Neuropathol Commun. 2019;7:128–16.

    PubMed  PubMed Central  Google Scholar 

  126. Bullock M, Lim G, Zhu Y, Åberg H, Kurdyukov S, Clifton-Bligh R. ETS factor ETV5 activates the mutant telomerase reverse transcriptase promoter in thyroid cancer. Thyroid. 2019;29:1623–33.

    CAS  PubMed  Google Scholar 

  127. Song YS, Yoo S-K, Kim HH, Jung G, Oh A-R, Cha J-Y, et al. Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer. Endocr. Relat. Cancer. 2019;26:629–41.

    CAS  PubMed  Google Scholar 

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Acknowledgements

Work in our laboratory is supported by NIH grants R01CA215733, R01CA226888, P01CA114046, P50CA174523, P30CA010815, the Department of Defense Melanoma Research Program (W81XWH-20-1-0356), the PA Department of Health and Martha W. Rogers Trust.

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Guterres, A.N., Villanueva, J. Targeting telomerase for cancer therapy. Oncogene 39, 5811–5824 (2020). https://doi.org/10.1038/s41388-020-01405-w

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