2026-06-14T03:29:39Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/83242024-11-29T15:12:38Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Bejarano, Leire author Bosso, Giuseppe author Louzame, Jessica author Serrano, Rosa author Gómez-Casero, Elena author Martinez Torrecuadrada, Jorge Luis author Martinez, Sonia author Blanco-Aparicio, Carmen author Pastor Fernandez, Joaquin author Blasco , MA author 2019-06-13 Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models. EMBO Mol Med. 2019 Jun 13. pii: e10292. 10.15252/emmm.201910292 1757-4684 1757-4676 EMBO molecular medicine 31196866 http://hdl.handle.net/20.500.12105/8324 ERK kinase TRF1 inhibitors drug resistance glioblastoma telomeres Multiple cancer pathways regulate telomere protection