Abstract SY35-03: Novel anti-tumor activity of targeted LSD1 inhibition

Abstract Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. These complexes include Histone Deacetylases (HDAC1/2) and Co-Repressor for Element-1-Silencing Transcription factor (CoREST). LSD1 mediated H3K4 demethylation can result in a repressive chromatin environment that silences gene expression and has been shown to play a role in development. LSD1 can interact with pluripotency factors in human embryonic stem cells and is essential for decommissioning enhancers in stem cell differentiation. Beyond embryonic settings, LSD1 is also critical for hematopoietic differentiation. LSD1 dysregulation plays a key role in cancer and LSD1 is overexpressed in multiple tumor types, including acute myeloid leukemia (AML). Recent literature suggests inhibition of LSD1 reactivates the all-trans retinoic acid differentiation pathway in AML. Together, these observations suggest LSD1 is an important regulator of the epigenome that modulates gene expression through post-translational modification of histones and its presence in transcriptional complexes. The current study describes the anti-tumor effects of a novel LSD1 inhibitor (GSK2879552). GSK2879552 is a potent, selective, mechanism-based irreversible inhibitor of LSD1 currently in clinical development. Screening of over 150 cancer cell lines revealed that while many tumor types appear resistant to LSD1 inhibition, specific tumor types were uniquely sensitive. For example, AML cells have a distinct requirement for LSD1, and LSD1 inhibition results in a prodifferentiation effect in this setting. Preclinical characterization of the anti-tumor activities of GSK2879552 both in vitro and in vivo in AML as well as the solid tumor setting will be discussed. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Ryan G. Kruger. Novel anti-tumor activity of targeted LSD1 inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY35-03. doi:10.1158/1538-7445.AM2014-SY35-03