Multiple cancer pathways regulate telomere protection
Ontology highlight
ABSTRACT:
SUBMITTER: Leire Bejarano
PROVIDER: S-SCDT-EMM-2019-10292 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Telomere maintenance is essential for cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are frequently found in cancer. Mutations in the telomeric sheltering complex, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition, however, direct targeting of the shelterin complex maybe a more effective strategy. We showed that genetic deletion of the TRF1 shelterin protein impairs tumor growth in lung cancer and glioblastoma (GBM) mouse models by 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, covering many Reactome pathways. We find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulate the effects of Trf1 genetic deletion, including induction of telomeric DNA damage. We show that both bRAF and ERK2 kinases phosphorylate TRF1 and that these modifications are essential for TRF1 location to telomeres. Finally, we describe drug combinations which synergistically block TRF1 inhibition in patient-derived glioblastoma xenograft models
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Project description: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.
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