Preclinical studies reveal that LSD 1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

Lung adenocarcinoma ( LUAD ) is the most prevalent subtype of non‐small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5‐year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine‐specific demethylase 1 ( LSD 1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD . Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD 1 as a novel therapeutic option for treating LUAD . The reversible LSD 1 inhibitor HCI ‐2509 significantly reduced cell growth with an IC 50 of 0.3–5 μ m in vitro, which was linked to an enhancement of histone 3 lysine methylation. Most importantly, growth arrest, as well as inhibition of the invasion capacities, was independent of the underlying driver mutations. Subsequent expression profiling revealed that the cell cycle and replication machinery were prominently affected after LSD 1 inhibition. In addition, our data provide evidence that LSD 1 blockade significantly interferes with EGFR downstream signaling. Finally, our in vitro results were confirmed by preclinical therapeutic approaches, including the use of two autochthonous transgenic LUAD mouse models driven by either EGFR or KRAS mutations. Importantly, LSD 1 inhibition resulted in significantly lower tumor formation and a strong reduction in tumor progression, which were independent of the underlying mutational background of the mouse models. Hence, our findings provide substantial evidence indicating that tumor growth of LUAD can be markedly decreased by HCI ‐2509 treatment, suggesting its use as a single agent maintenance therapy or combined therapeutical application in novel concerted drug approaches.