Therapeutic inhibition of TRF1 impairs the growth of p53‐deficient K‐RasG12V‐induced lung cancer by induction of telomeric DNA damage | EMBO Molecular Medicine
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‐RasG12V‐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 Trf1deletion 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‐RasG12V‐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.
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