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Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles

Introduction: Improved therapies for glioblastoma (GBM) are desperately needed and require preclinical evaluation in models that capture tumor heterogeneity and intrinsic resistance seen in patients. Epigenetic alterations have been well documented in GBM and lysine-specific demethylase 1 (LSD1/KDM1A) is amongst the chromatin modifiers implicated in stem cell maintenance, growth and differentiation. Pharmacological inhibition of LSD1 is clinically relevant, with numerous compounds in various phases of preclinical and clinical development, but an evaluation and comparison of LSD1 inhibitors in patient-derived GBM models is lacking.

Methods: To assess concordance between knockdown of LSD1 and inhibition of LSD1 using a prototype inhibitor in GBM, we performed RNA-seq to identify genes and biological processes associated with inhibition. Efficacy of various LSD1 inhibitors was assessed in nine patient-derived glioblastoma stem cell (GSC) lines and an orthotopic xenograft mouse model.

Results: LSD1 inhibitors had cytotoxic and selective effects regardless of GSC radiosensitivity or molecular subtype. In vivo, LSD1 inhibition via GSK-LSD1 led to a delayed reduction in tumor burden; however, tumor regrowth occurred. Comparison of GBM lines by RNA-seq was used to identify genes that may predict resistance to LSD1 inhibitors. We identified five genes that correlate with resistance to LSD1 inhibition in treatment resistant GSCs, in GSK-LSD1 treated mice, and in GBM patients with low LSD1 expression.

Conclusion: Collectively, the growth inhibitory effects of LSD1 inhibition across a panel of GSC models and identification of genes that may predict resistance has potential to guide future combination therapies.

 

Comments:

Abstract: This study aimed to evaluate the efficacy of LSD1 inhibitors in patient-derived glioblastoma models and identify potential resistance mechanisms. LSD1, a chromatin modifier involved in stem cell maintenance and differentiation, has been implicated in glioblastoma progression. However, a comprehensive evaluation and comparison of LSD1 inhibitors in patient-derived models is lacking.

The researchers utilized RNA-seq analysis to compare the effects of LSD1 knockdown and inhibition in glioblastoma cells. The study also assessed the efficacy of various LSD1 inhibitors in nine patient-derived glioblastoma stem cell lines and an orthotopic xenograft mouse model.

The results showed that LSD1 inhibitors exhibited cytotoxic effects and selectivity across different glioblastoma stem cell lines, regardless of radiosensitivity or molecular subtype. In an in vivo mouse model, LSD1 inhibition using GSK-LSD1 resulted in a delayed reduction in tumor burden; however, tumor regrowth eventually occurred.

To identify potential resistance mechanisms, the researchers performed RNA-seq analysis and identified five genes that correlated with resistance to LSD1 inhibition. These genes were found to be associated with treatment-resistant glioblastoma stem cells, GSK-LSD1-treated mice, and GBM patients with low LSD1 expression.

The findings suggest that LSD1 inhibition has growth inhibitory effects in a panel of glioblastoma stem cell models. Moreover, the identification of genes that may predict resistance to LSD1 inhibitors could guide the development of future combination therapies for glioblastoma treatment.

Overall, this study provides valuable insights into the therapeutic potential of LSD1 inhibitors and highlights the importance of understanding resistance mechanisms in order to improve glioblastoma treatment strategies.