Research Paper Volume 12, Issue 6 pp 4794—4814
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
- 1 Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
- 2 Girona Biomedical Research Institute (IDIBGI), Girona, Spain
- 3 StemTek Therapeutics, Bilbao, Spain
- 4 Medical Oncology, Catalan Institute of Oncology (ICO), Girona, Spain
- 5 Department of Medical Sciences, Medical School University of Girona, Girona, Spain
- 6 Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain
- 7 Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI), Girona, Spain
- 8 Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain
- 9 ICREA, Barcelona, Spain
- 10 Centre de Recerca Matemàtica (CRM), Barcelona, Spain
- 11 Departament de Matemàtiques, Universitat Autònoma de Barcelona, Barcelona, Spain
- 12 Barcelona Graduate School of Mathematics (BGSMath), Barcelona, Spain
- 13 Institute of Research, Development and Innovation in Biotechnology of Elche (IDiBE) and Molecular and Cell Biology Institute (IBMC), Miguel Hernández University (UMH), Elche, Spain
Received: December 21, 2019 Accepted: February 5, 2020 Published: March 18, 2020
https://doi.org/10.18632/aging.102887How to Cite
Copyright © 2020 Cuyàs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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.