title: Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.
abstract: Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-Ras(G12V)-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: García-Beccaria
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marinela
authors.initials: M
authors.lastname: Méndez-Pertuz
authors.affiliation: Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Martínez
authors.affiliation: Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco-Aparicio
authors.affiliation: Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Molecular Imaging Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Mulero
authors.affiliation: Experimental Oncology, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ambrogio
authors.affiliation: Animal Surgery and Medicine Department, Faculty of Veterinary Science, Complutense University of Madrid, Madrid, Spain.
authors.forename: Juana M
authors.initials: JM
authors.lastname: Flores
authors.affiliation: Microscopy Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Megias
authors.affiliation: Molecular Imaging Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.affiliation: Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain mblasco@cnio.es.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004195:Disease Models, Animal; D017353:Gene Deletion; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics*; D020125:Mutation, Missense; D015689:Oncogene Protein p21(ras) / Q000235:genetics*; D016019:Survival Analysis; D016615:Telomere / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
chemical_list: D050505:Mutant Proteins; D035321:Telomeric Repeat Binding Protein 1; D016159:Tumor Suppressor Protein p53; D015689:Oncogene Protein p21(ras)
keywords: TRF1; cancer; drug development; shelterin; telomeres