1. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC
- Author
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Thau F. Ho, Yan Liu, Xinrong Tian, Patrick McDevitt, Michael Butticello, Timothy K. Hart, Kimberly N. Smitheman, David Soong, Jessica L. Schneck, Peter J. Tummino, Christine L. Hann, Glenn S. Van Aller, Yuchen Bai, Nestor O. Concha, Kasparec Jiri, Melissa B. Pappalardi, Christopher L. Carpenter, Mcnulty Kenneth C, Kelly Federowicz, Jeffrey D. Carson, William H. Miller, Johnson Neil W, Chandrashekhar D. Kamat, Rouse Meagan B, Charles F. McHugh, Michael T. McCabe, Ryan G. Kruger, Dashyant Dhanak, Helai P. Mohammad, Michelle Crouthamel, Yan Degenhardt, William G. Bonnette, and Shelby A. Gorman
- Subjects
Cyclopropanes ,Cancer Research ,animal structures ,Lung Neoplasms ,Molecular Sequence Data ,Administration, Oral ,Antineoplastic Agents ,Benzoates ,Article ,Epigenesis, Genetic ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epigenetics ,Enzyme Inhibitors ,Cell Proliferation ,Histone Demethylases ,biology ,Cancer ,KDM1A ,Biological activity ,Cell Biology ,DNA Methylation ,medicine.disease ,Small Cell Lung Carcinoma ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,chemistry ,Biochemistry ,Oncology ,Cell culture ,biology.protein ,Cancer research ,Demethylase ,Growth inhibition ,DNA hypomethylation - Abstract
SummaryEpigenetic 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.
- Published
- 2015