title: Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.
abstract: Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers, yet whether it can be exploited therapeutically remains unknown. Loss of the chromatin-remodeling protein ATRX associates with ALT in cancers. Here, we show that ATRX loss compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. zou.lee@mgh.harvard.edu rlflynn@bu.edu.
authors.forename: Rachel Litman
authors.initials: RL
authors.lastname: Flynn
authors.affiliation: Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Kelli E
authors.initials: KE
authors.lastname: Cox
authors.affiliation: Laboratoire de Radiopathologie, UMR 967, Institut de Radiobiologie Cellulaire et Moleculaire, CEA Fontenay-aux-Roses, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Jeitany
authors.affiliation: Deparment of Surgery and Brain Tumor Center, Massachusetts General Hospital, Boston, MA 02115, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Alysia R
authors.initials: AR
authors.lastname: Bryll
authors.affiliation: Departments of Pharmacology & Experimental Therapeutics, and Medicine, Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ganem
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.affiliation: Laboratoire de Radiopathologie, UMR 967, Institut de Radiobiologie Cellulaire et Moleculaire, CEA Fontenay-aux-Roses, France.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Pineda
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Suvà
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Laboratoire de Radiopathologie, UMR 967, Institut de Radiobiologie Cellulaire et Moleculaire, CEA Fontenay-aux-Roses, France.
authors.forename: Francois D
authors.initials: FD
authors.lastname: Boussin
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. zou.lee@mgh.harvard.edu rlflynn@bu.edu.
authors.forename: Lee
authors.initials: L
authors.lastname: Zou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000188:drug therapy / Q000235:genetics; D006367:HeLa Cells; D059765:Homologous Recombination; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics; D000071156:Promyelocytic Leukemia Protein; D011719:Pyrazines / Q000494:pharmacology*; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D051716:Replication Protein A / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000075924:X-linked Nuclear Protein
chemical_list: C560580:3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide; D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011719:Pyrazines; D022661:RNA, Untranslated; C497167:RPA1 protein, human; D051716:Replication Protein A; D013450:Sulfones; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein