Pharmacological Inhibition of LSD1/KDM1A in Diffuse Midline Glioma Models and Impact on Kinase Signaling

Diffuse Midline Gliomas (DMG) occur in the midline structures of the brain such as the brainstem. DMG, a subset of pediatric high-grade gliomas (pHGGs), confers poor prognosis in children with survival rates below two years post-diagnosis. This is heavily due to limited treatment options as radiation and chemotherapy are only temporarily effective and surgery pose high risks. DMG are characterized by histone mutations typically occurring in histone 3.1 and 3.3 alleles, with about more than 80% of patients containing the H3K27 mutation. Recent publications, highlight epigenetic modulators as promising cancer-specific targets emphasizing their potential as a novel therapeutic strategy. Epigenetic modulator, lysine specific demethylase 1 (LSD1) is a histone demethylase. It’s function demethylates mono- and di-methyl marks on H3K4 and H3K9 residues. This demethylase activity can impact gene transcription and overall gene expression, where dysregulated LSD1 expression has been found to be implicated in tumorigenesis highlighting LSD1 as a possible therapeutic target. Our lab’s past work has shown that pharmacological inhibition or gene silencing of LSD1 slowed DMG cell growth. However, while pharmacological inhibition of LSD1 is promising, further optimization is needed to mitigate any off-target effects that may alter drug response and impact the anti-tumor response. It has been seen in prior studies that LSD1 can interact with kinase signaling pathways in other cancer models. Our lab has shown that LSD1 may regulate kinase signaling pathways and that LSD1 inhibition and LSD1 knockdown share biological implications on cellular processes in adult glioblastoma models. Receptor tyrosine kinases (RTKs) notably, have a frequent number of genetic alterations reported in pediatric and adult glioblastoma. However, the interaction between LSD1 and kinase signaling networks in DMG remains largely unknown. Therefore, I assessed the crosstalk between clinically relevant pharmacological LSD1 inhibitor, bomedemstat, and the mitogen-activated protein kinase (MAPK) signaling pathway aiming to uncover potential compensatory resistance mechanisms, in this study. Through intensive screening, I have revealed that LSD1 inhibition with bomedemstat increases MAPK kinase signaling at subtoxic concentrations limiting cell cytotoxicity and drug efficacy in our DMG models. With dual LSD1 and kinase inhibition, we saw synergistic cytotoxicity at subtoxic concentrations. This study helps bridge the gap in knowledge between LSD1 inhibition and aberrant kinase signaling in DMGs, and highlights the benefit of combination therapies with LSD1 and kinase inhibitors as a possible therapeutic strategy.