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Published on: July 21, 2018
Antitumor activity of LSD1 inhibitors in lung cancer
Helai P Mohammad1, Ryan G Kruger1
1Cancer Epigenetics, GlaxoSmithKline , Collegeville, PA, USA.
Abstract:
Epigenetic machinery have become a major focus for new targeted cancer therapies. Our previous report described the discovery and biological activity of a potent, selective, orally bioavailable, irreversible inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) was sensitive to LSD1 inhibition. The SCLC lines that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. This targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC.
Insights
Lysine Demethylase 1 (LSD1) inhibition shows promise for treating small cell lung carcinoma (SCLC). A novel drug, GSK2879552, effectively inhibits LSD1 and may be predicted by DNA hypomethylation.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Epigenetic regulators are emerging targets for novel cancer therapies.
- Lysine Demethylase 1 (LSD1) is a key epigenetic enzyme.
- GSK2879552 is a potent, selective, orally bioavailable, irreversible LSD1 inhibitor.
Purpose of the Study:
- To evaluate the efficacy of LSD1 inhibition in various cancer types.
- To identify potential predictive biomarkers for LSD1 inhibitor response.
- To assess the therapeutic potential of GSK2879552 in small cell lung carcinoma (SCLC).
Main Methods:
- Cell proliferation screening across multiple tumor types.
- Treatment of SCLC cell lines with GSK2879552.
- DNA methylation analysis using a signature set of probes.
Main Results:
- Small cell lung carcinoma (SCLC) cell lines demonstrated sensitivity to LSD1 inhibition.
- GSK2879552 treatment led to growth inhibition in sensitive SCLC lines.
- Sensitive SCLC lines exhibited DNA hypomethylation, suggesting a predictive biomarker.
Conclusions:
- LSD1 inhibition represents a promising targeted therapy for SCLC.
- DNA hypomethylation may serve as a predictive biomarker for LSD1 inhibitor efficacy.
- The combination of targeted LSD1 inhibition and a predictive biomarker offers a novel therapeutic strategy for SCLC.
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