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Research Article Free access | 10.1172/JCI32461
1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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1Experimental Chemotherapy Laboratory, 2Pathology Laboratory, 3Laboratory “D,” and 4Biostatistic Laboratory, Regina Elena Cancer Institute, Rome, Italy. 5Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom. 6Department of Oncology, “Mario Negri” Institute for Pharmacological Research, Milan, Italy. 7Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center, Madrid, Spain. 8Fondo Edo Tempia, Biella, Italy. 9Laboratory of Molecular Biology of the Cell, CNRS UMR5239, IFR128, University of Lyon, Faculté de Médecine Lyon-Sud, Oullins, France. 10Service “Biologie des Tumeurs Solides — Génomique — Protéomique,” Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre Bénite, France. 11Experimental Medicine and Pathology, Department II, S. Andrea Hospital, Rome, Italy.
Address correspondence to: Annamaria Biroccio, Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, via delle Messi d’Oro 156, 00158 Rome, Italy. Phone: 39-0652662569; Fax: 39-0652662592; E-mail: biroccio@ifo.it.
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Published October 11, 2007 - More info
Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors γ-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA–binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.