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.
Highlights
The transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells [1,2,3,4], is causally related to tumor initiation, aggressiveness, and metastasis likely due to its ability to induce and maintain the stemness of cancer stem cells (CSC) [5, 6]
We evaluated the clinical relevance of iadademstat as a novel anti-SOX2 epigenetic breast cancer therapy by assessing its ability to impact both the expression of SOX2 and the tumorsphere-forming capacity of CSClike cells derived from breast cancer patient-derived xenografts (PDX)
We provide the first evidence that the clinically proven inhibitor of LSD1 iadademstat can be used to circumvent the challenge of pharmacologically manipulating the epigenetic re-activation of SOX2 that causes a subpopulation of tumor cells to shift towards a CSC state, which has constrained the clinical relevance of SOX2-centered therapeutic strategies in major cancer types such as breast cancer
Summary
The transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells [1,2,3,4], is causally related to tumor initiation, aggressiveness, and metastasis likely due to its ability to induce and maintain the stemness of cancer stem cells (CSC) [5, 6]. Targeting of SOX2-related upstream/ downstream signaling pathways has become a more plausible approach, and pharmacological blockade of either the FBXW2-MSX2 axis with pevonedistat [12], the EGFR-STAT3 pathway with the cationic triphenylmethane pharmacophore gentian violet [13], or EGFR/SRC/AKT signaling with the EGFR inhibitors gefitinib and erlotinib and the Src inhibitor dasatinib [14], have been proposed as strategies to target human cancers with SOX2 overexpression. The aforementioned strategies mostly target the proximal promoters of the SOX2 gene driving SOX2 expression in the differentiated states of cancer cells, and epigenetic re-activation of stemnessspecific enhancers that cause a subpopulation of tumor cells to shift towards a CSC state is unaffected Such an approach can be achieved by inactivation of lysine-specific demethylase 1 (LSD1/KDM1A), a flavin adenine dinucleotide (FAD)-
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