Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

Abstract

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 (LSD1) 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 LSD1 as a novel therapeutic option for treating LUAD. The reversible LSD1 inhibitor HCI‐2509 significantly reduced cell growth with an IC 50 of 0.3–5 μm 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 LSD1 inhibition. In addition, our data provide evidence that LSD1 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, LSD1 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.

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

“…LSD1 dysfunction is also associated with the development of ALL (acute lymphoblastic leukemia) and AML (acute myeloid leukemia) [22–24]. Preclinical studies have revealed that LSD1 inhibition could suppress tumor growth of lung adenocarcinoma independent on driver mutations [25]. Expression profiling reveals that LSD1 inhibition mainly affects replication machinery and cell cycle, and interrupts downstream signaling of EGFR (epidermal growth factor receptor).…”

Four long noncoding RNAs act as biomarkers in lung adenocarcinoma

“…Many new methods are currently used to diagnose and treat this disease [ 3 ]. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase are two key oncogenes that trigger lung adenocarcinoma (LUAD) [ 4 , 5 , 6 ]. Despite great achievements, overall survival (OS) time for LUAD is less than 5 years because of aggressive properties of the tumor and a lack of effective early diagnostic and prognostic biomarkers [ 7 ].…”

Identification of a long non‑coding RNA signature for predicting prognosis and biomarkers in lung adenocarcinoma

“…Lung cancer can be categorized into two main histological subtypes, non-small-cell lung cancer (NSCLC) and small-cell lung cancer, accounting for ~85% and ~15% of cases, respectively (2,3). Lung adenocarcinoma (LUAD) is one of the major subtypes of NSCLC with a low 5-year survival rate of ~20% in the USA (4,5). It is currently understood that two of the driver oncogenes involved in tumorigenesis and progression of LUAD are epidermal growth factor receptor and anaplastic lymphoma kinase (6)(7)(8).…”