The LSD1 inhibitor iadademstat (ORY-1001) targets SOX2-driven breast cancer stem cells: a potential epigenetic therapy in luminal-B and HER2-positive breast cancer subtypes

Aging (Albany NY). 2020 Mar 18;12(6):4794-4814. doi: 10.18632/aging.102887. Epub 2020 Mar 18.


SOX2 is a core pluripotency-associated transcription factor causally related to cancer initiation, aggressiveness, and drug resistance by driving the self-renewal and seeding capacity of cancer stem cells (CSC). Here, we tested the ability of the clinically proven inhibitor of the lysine-specific demethylase 1 (LSD1/KDM1A) iadademstat (ORY-100) to target SOX2-driven CSC in breast cancer. Iadademstat blocked CSC-driven mammosphere formation in breast cancer cell lines that are dependent on SOX2 expression to maintain their CSC phenotype. Iadademstat prevented the activation of an LSD1-targeted stemness-specific SOX2 enhancer in CSC-enriched 3-dimensional spheroids. Using high-throughput transcriptional data available from the METABRIC dataset, high expression of SOX2 was significantly more common in luminal-B and HER2-enriched subtypes according to PAM50 classifier and in IntClust1 (high proliferating luminal-B) and IntClust 5 (luminal-B and HER2-amplified) according to integrative clustering. Iadademstat significantly reduced mammospheres formation by CSC-like cells from a multidrug-resistant luminal-B breast cancer patient-derived xenograft but not of those from a treatment-naïve luminal-A patient. Iadademstat reduced the expression of SOX2 in luminal-B but not in luminal-A mammospheres, likely indicating a selective targeting of SOX2-driven CSC. The therapeutic relevance of targeting SOX2-driven breast CSC suggests the potential clinical use of iadademstat as an epigenetic therapy in luminal-B and HER2-positive subtypes.

Keywords: breast cancer; cancer stem cells; epigenetics; patient-derived xenografts; reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Enzyme Inhibitors / administration & dosage*
  • Epigenesis, Genetic / drug effects*
  • Female
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism*
  • Humans
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • SOXB1 Transcription Factors / metabolism*


  • Enzyme Inhibitors
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Histone Demethylases
  • KDM1A protein, human