title: A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC.
abstract: Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity.
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Helai P
authors.initials: HP
authors.lastname: Mohammad
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Smitheman
authors.affiliation: Oncology Department, Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: Chandrashekhar D
authors.initials: CD
authors.lastname: Kamat
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: David
authors.initials: D
authors.lastname: Soong
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Federowicz
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Van Aller
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Jess L
authors.initials: JL
authors.lastname: Schneck
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Carson
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Butticello
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Bonnette
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Shelby A
authors.initials: SA
authors.lastname: Gorman
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Degenhardt
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCabe
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Pappalardi
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kasparec
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tian
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: McNulty
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Meagan
authors.initials: M
authors.lastname: Rouse
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: McDevitt
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Thau
authors.initials: T
authors.lastname: Ho
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Crouthamel
authors.affiliation: Safety Assessment Department, GlaxoSmithKline, Upper Merion, PA 19406, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Hart
authors.affiliation: Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Nestor O
authors.initials: NO
authors.lastname: Concha
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: McHugh
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Carpenter
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Neil W
authors.initials: NW
authors.lastname: Johnson
authors.affiliation: Oncology Department, Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.affiliation: Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA. Electronic address: ryan.g.kruger@gsk.com.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Kruger
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; C000602008:GSK2879552; D056466:Histone Demethylases; C495195:KDM1A protein, human