Title:
|
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
|
Author:
|
Cuyàs, Elisabet; Gumuzio, Juan; Verdura, Sara; Brunet, Joan; Bosch-Barrera, J; Martin-Castillo, Begoña; Alarcón Cor, Tomás; Encinar, José Antonio; Martin, Ángel G.; Menendez, Javier A.
|
Abstract:
|
Altres ajuts: Fundació Oncolliga Girona, Generalitat Valenciana (PROMETEO/2016/006) |
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. |
Subject(s):
|
-Epigenetics -Reprogramming -Cancer stem cells -Breast cancer -Patient-derived xenografts |
Rights:
|
open access
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
https://creativecommons.org/licenses/by/4.0/ |
Document type:
|
Article |
Published by:
|
|
Share:
|
|
Uri:
|
https://ddd.uab.cat/record/227673
|