2. Academic Validation
  3. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC

  • Cancer Cell. 2015 Jul 13;28(1):57-69. doi: 10.1016/j.ccell.2015.06.002.
Helai P Mohammad 1,  Kimberly N Smitheman 1,  Chandrashekhar D Kamat 2,  David Soong 1,  Kelly E Federowicz 1,  Glenn S Van Aller 1,  Jess L Schneck 3,  Jeffrey D Carson 3,  Yan Liu 1,  Michael Butticello 1,  William G Bonnette 3,  Shelby A Gorman 1,  Yan Degenhardt 1,  Yuchen Bai 1,  Michael T McCabe 1,  Melissa B Pappalardi 1,  Jiri Kasparec 1,  Xinrong Tian 1,  Kenneth C McNulty 1,  Meagan Rouse 1,  Patrick McDevitt 3,  Thau Ho 3,  Michelle Crouthamel 1,  Timothy K Hart 4,  Nestor O Concha 3,  Charles F McHugh 1,  William H Miller 1,  Dashyant Dhanak 1,  Peter J Tummino 1,  Christopher L Carpenter 1,  Neil W Johnson 1,  Christine L Hann 2,  Ryan G Kruger 5
Affiliations

Affiliations

  • 1 Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • 2 Oncology Department, Johns Hopkins University, Baltimore, MD 21231, USA.
  • 3 Platform Technology and Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • 4 Safety Assessment Department, GlaxoSmithKline, Upper Merion, PA 19406, USA.
  • 5 Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA. Electronic address: ryan.g.kruger@gsk.com.
PMID: 26175415 DOI: 10.1016/j.ccell.2015.06.002
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.

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