Therapeutic inhibition of TRF1 impairs the growth of p53‐deficient K‐RasG12V‐induced lung cancer by induction of telomeric DNA damage

• Published in: EMBO molecular medicine Vol. 7; no. 7; pp. 930 - 949
• Main Authors: García‐Beccaria, María, Martínez, Paula, Méndez‐Pertuz, Marinela, Martínez, Sonia, Blanco‐Aparicio, Carmen, Cañamero, Marta, Mulero, Francisca, Ambrogio, Chiara, Flores, Juana M, Megias, Diego, Barbacid, Mariano, Pastor, Joaquín, Blasco, Maria A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2015; John Wiley & Sons, Ltd; Springer Nature
• Subjects: Animals; Apoptosis; cancer; Cell Cycle Checkpoints - drug effects; Cell Proliferation - drug effects; Disease Models, Animal; DNA Damage; drug development; EMBO03; EMBO09; Gene Deletion; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Mice; Mutant Proteins - genetics; Mutation, Missense; Oncogene Protein p21(ras) - genetics; Research Article; shelterin; Survival Analysis; Telomere - metabolism; telomeres; Telomeric Repeat Binding Protein 1 - antagonists & inhibitors; Telomeric Repeat Binding Protein 1 - genetics; Treatment Outcome; TRF1; Tumor Suppressor Protein p53 - deficiency; drug development; shelterin; cancer; TRF1; telomeres
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404497

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.
Synopsis
Activation of rapid telomere uncapping by inhibition of TRF1 can block growth of already established
K‐Ras
‐induced lung cancers independently of telomere length, and without seriously affecting mouse survival or tissue function.
Genetic
Trf1
ablation impairs the growth of p53‐null
K‐Ras
G12V
‐induced lung carcinomas and increases mouse survival independently of telomere length.
Inhibition of TRF1 binding to telomeres can be achieved
in vivo
by small molecules and blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.
Ubiquitous TRF1 downregulation allows tissue function with limited side effects.
Graphical Abstract
Activation of rapid telomere uncapping by inhibition of TRF1 can block growth of already established
K‐Ras
‐induced lung cancers independently of telomere length, and without seriously affecting mouse survival or tissue function.