Combined Inhibition of Lysine-Specific Demethylase 1 and Kinase Signaling as a Preclinical Treatment Strategy in Glioblastoma

Authors

Lea M Stitzlein
Deokhwa Nam
Faith A Hernandez
Kareena H Patel
Alaina Poche
Huaxian Ma
Katie Impelman
Joy Gumin
Heping Wang
Jing Wang
Samantha Gadd
Wafik Zaky
Oren Becher
Richard W Dudley
Frederick F Lang
Gangadhara R Sareddy
Joya Chandra

Language

English

Publication Date

1-1-2025

Journal

Neuro-Oncology Advances

DOI

10.1093/noajnl/vdaf246

PMID

41497449

PMCID

PMC12768500

PubMedCentral® Posted Date

11-20-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Lysine-specific demethylase 1 (LSD1) is overexpressed in glioblastoma, contributing to tumor growth and treatment resistance. LSD1 inhibitors have shown preclinical promise but have had limited clinical development for glioblastoma. Given the frequent kinase pathway alterations seen in glioblastoma, the interplay between LSD1 inhibition and kinase signaling pathways was investigated.

Methods: Glioblastoma stem cell (GSC) lines and normal human astrocytes (NHAs) were treated with catalytic LSD1 inhibitors, NCD38 and bomedemstat, and the LSD1 scaffolding inhibitor, seclidemstat alone and in combination with kinase inhibitors, including osimertinib, afatinib, and ulixertinib. The effect on cell viability, proliferation, and neurosphere formation was assessed, and synergy scores were calculated using Bliss synergy models. Kinase signaling was analyzed and in vivo efficacy was evaluated in orthotopic xenograft models.

Results: LSD1 knockdown and seclidemstat reduced kinase signaling, while catalytic LSD1 inhibitors increased kinase activity or had no effect. Catalytic LSD1 inhibitors combined with kinase inhibitors, synergistically reduced GSC viability and proliferation while sparing NHAs. Combination treatment consistently reduced phospho-S6 ribosomal protein levels in three different GSC lines, and basal phospho-S6 ribosomal protein levels across the GSCs and the NHAs were negatively correlated with a synergistic response. The generation of an NCD38-resistant GSC showed increased kinase activity and was associated with enhanced osimertinib sensitivity. Combined treatment with NCD38 and osimertinib in glioblastoma-bearing mice delayed tumor growth and improved survival outcomes.

Discussion: These findings provide a rationale for further investigation of combination therapies of catalytic inhibitors of LSD1 and EGFR and dual-targeted inhibitors to overcome resistance and improve outcomes.

Keywords

glioblastoma stem cell, kinase signaling, lysine specific demethylase-1, osimertinib

Published Open-Access

yes

Recommended Citation

Stitzlein, Lea M; Nam, Deokhwa; Hernandez, Faith A; et al., "Combined Inhibition of Lysine-Specific Demethylase 1 and Kinase Signaling as a Preclinical Treatment Strategy in Glioblastoma" (2025). Faculty, Staff and Student Publications. 5444.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5444