Universität zu Köln

Macheleidt, Iris F., Dalvi, Priya S., Lim, So-Young, Meemboor, Sonja, Meder, Lydia ORCID: 0000-0002-9547-5812, Kaesgen, Olivia, Mueller, Marion, Kleemann, Karolin, Wang, Lingyu, Nuernberg, Peter, Ruesseler, Vanessa, Schaefer, Stephan C., Mahabir, Esther, Buettner, Reinhard and Odenthal, Margarete (2018). Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations. Mol. Oncol., 12 (11). S. 1965 - 1980. HOBOKEN: WILEY. ISSN 1878-0261

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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 IC50 of 0.3-5 mu min 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Macheleidt, Iris F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dalvi, Priya S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lim, So-Young UNSPECIFIED UNSPECIFIED UNSPECIFIED Meemboor, Sonja UNSPECIFIED UNSPECIFIED UNSPECIFIED Meder, Lydia UNSPECIFIED orcid.org/0000-0002-9547-5812 UNSPECIFIED Kaesgen, Olivia UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleemann, Karolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Lingyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruesseler, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaefer, Stephan C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mahabir, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-167943
DOI:	10.1002/1878-0261.12382
Journal or Publication Title:	Mol. Oncol.
Volume:	12
Number:	11
Page Range:	S. 1965 - 1980
Date:	2018
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1878-0261
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPITHELIAL-MESENCHYMAL TRANSITION; DEMETHYLASE 1; HISTONE METHYLATION; TRANSCRIPTIONAL ACTIVITY; EPIGENETIC THERAPY; CANCER-THERAPY; CELLS; GENE; ACTIVATION; METHYLTRANSFERASES Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16794