2026-05-22T00:32:23Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/100892024-11-29T21:42:09Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc García-Beccaria, María author Martinez Rodriguez, Paula author Méndez-Pertuz, Marinela author Martinez, Sonia author Blanco-Aparicio, Carmen author Cañamero, Marta author Mulero, Francisca author Ambrogio, Chiara author Flores, Juana M author Megias Vazquez, Diego author Barbacid, Mariano author Pastor Fernandez, Joaquin author Blasco, MA author 2015-07-07 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. EMBO Mol Med. 2015 ;7(7):930-49. 10.15252/emmm.201404497 1757-4684 1757-4676 EMBO molecular medicine 25971796 http://hdl.handle.net/20.500.12105/10089 TRF1 cancer drug development shelterin telomeres Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage