Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/10089
Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage
García-Beccaria, María | Martinez Rodriguez, Paula CNIO | Méndez-Pertuz, Marinela | Martinez, Sonia CNIO | Blanco-Aparicio, Carmen CNIO | Cañamero, Marta | Mulero, Francisca CNIO | Ambrogio, Chiara | Flores, Juana M | Megias Vazquez, Diego CNIO | Barbacid, Mariano CNIO | Pastor Fernández, Joaquín CNIO | Blasco, MA CNIO
EMBO Mol Med. 2015 ;7(7):930-49.
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.
Animals | Apoptosis | Cell Cycle Checkpoints | Cell Proliferation | Disease Models, Animal | Gene Deletion | Lung Neoplasms | Mice | Mutant Proteins | Mutation, Missense | Oncogene Protein p21(ras) | Survival Analysis | Telomere | Telomeric Repeat Binding Protein 1 | Treatment Outcome | Tumor Suppressor Protein p53 | DNA Damage
We are indebted to R. Serrano for animal care. We thank C. Guerra, R. Blasco, and D. Santamaria for scientific and technical advice. M.A.B.'s laboratory is funded with the Spanish Ministry of Science and Innovation, projects SAF2008-05384 and 2007-A-200950 (TELOMARKER), European Research Council Advanced grant GA#232854, the Korber Foundation, Fundacion Botin, and Fundacion Lilly.
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