Open AccessTherapeutic inhibition of TRF 1 impairs the growth of p53 ‐deficient K‐Ras G12V ‐ induced lung cancer by induction of telomeric DNA damage
Author(s) -
GarcíaBeccaria María,
Martínez Paula,
MéndezPertuz Marinela,
Martínez Sonia,
BlancoAparicio Carmen,
Cañamero Marta,
Mulero Francisca,
Ambrogio Chiara,
Flores Juana M,
Megias Diego,
Barbacid Mariano,
Pastor Joaquín,
Blasco Maria A
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404497
Subject(s) - cancer research , cancer , lung cancer , cell growth , mutation , microbiology and biotechnology , biology , chemistry , medicine , genetics , gene
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 TRF 1 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 TRF 1 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.