title: Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.
abstract: Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.
authors.affiliation: Pharmacology Graduate Training Program, Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Gardner
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lok
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Valentina E
authors.initials: VE
authors.lastname: Schneeberger
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Desmeules
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Linde A
authors.initials: LA
authors.lastname: Miles
authors.affiliation: Louis V. Gerstner, Jr., Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Paige K
authors.initials: PK
authors.lastname: Arnold
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Ni
authors.affiliation: Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Khodos
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Thuyen
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Ribich
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Rekhtman
authors.affiliation: Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Pierre P
authors.initials: PP
authors.lastname: Massion
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudinc@mskcc.org.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: poirierj@mskcc.org.
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D051879:Twist-Related Protein 1 / Q000502:physiology
chemical_list: D009687:Nuclear Proteins; C576668:SLFN11 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: EPZ011989; EZH2; SLFN11; TWIST1; acquired resistance; cisplatin; etoposide; patient-derived xenograft; small cell lung cancer