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Preclinical studies reveal that LSD1 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 (LSD1) is an ep...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210049/ https://www.ncbi.nlm.nih.gov/pubmed/30220105 http://dx.doi.org/10.1002/1878-0261.12382 |
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author | Macheleidt, Iris F. Dalvi, Priya S. Lim, So‐Young Meemboor, Sonja Meder, Lydia Käsgen, Olivia Müller, Marion Kleemann, Karolin Wang, Lingyu Nürnberg, Peter Rüsseler, Vanessa Schäfer, Stephan C. Mahabir, Esther Büttner, Reinhard Odenthal, Margarete |
author_facet | Macheleidt, Iris F. Dalvi, Priya S. Lim, So‐Young Meemboor, Sonja Meder, Lydia Käsgen, Olivia Müller, Marion Kleemann, Karolin Wang, Lingyu Nürnberg, Peter Rüsseler, Vanessa Schäfer, Stephan C. Mahabir, Esther Büttner, Reinhard Odenthal, Margarete |
author_sort | Macheleidt, Iris F. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6210049 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62100492018-11-08 Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations Macheleidt, Iris F. Dalvi, Priya S. Lim, So‐Young Meemboor, Sonja Meder, Lydia Käsgen, Olivia Müller, Marion Kleemann, Karolin Wang, Lingyu Nürnberg, Peter Rüsseler, Vanessa Schäfer, Stephan C. Mahabir, Esther Büttner, Reinhard Odenthal, Margarete Mol Oncol Research Articles 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. John Wiley and Sons Inc. 2018-10-13 2018-11 /pmc/articles/PMC6210049/ /pubmed/30220105 http://dx.doi.org/10.1002/1878-0261.12382 Text en © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Macheleidt, Iris F. Dalvi, Priya S. Lim, So‐Young Meemboor, Sonja Meder, Lydia Käsgen, Olivia Müller, Marion Kleemann, Karolin Wang, Lingyu Nürnberg, Peter Rüsseler, Vanessa Schäfer, Stephan C. Mahabir, Esther Büttner, Reinhard Odenthal, Margarete Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
title | Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
title_full | Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
title_fullStr | Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
title_full_unstemmed | Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
title_short | Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
title_sort | preclinical studies reveal that lsd1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210049/ https://www.ncbi.nlm.nih.gov/pubmed/30220105 http://dx.doi.org/10.1002/1878-0261.12382 |
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