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

EMBO Molecular Medicine

María García-Beccaria¹  Paula Martínez¹  Marinela Méndez-Pertuz¹  Sonia Martínez²  Carmen Blanco-Aparicio²  Marta Cañamero⁴  Francisca Mulero⁷  Chiara Ambrogio³  Juana M Flores⁵  Diego Megias⁶  Mariano Barbacid⁷  Joaquín Pastor² 

[1]Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

[2]Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

[3]Experimental Oncology, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

[4]Histopathology Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

[5]Animal Surgery and Medicine Department, Faculty of Veterinary Science, Complutense University of Madrid, Madrid, Spain

[6]Microscopy Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

[7]Molecular Imaging Unit, Biotechnology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

关键词: cancer;    drug development;    shelterin;    telomeres;    TRF1;   

DOI  :  10.15252/emmm.201404497

来源: Wiley

【 摘 要 】

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.

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.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.