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A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC
Helai P Mohammad1, Kimberly N Smitheman1, Chandrashekhar D Kamat2
1Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
Abstract:
Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples 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.
Insights
A new drug, GSK2879552, targets Lysine Demethylase 1 (LSD1) to treat cancer. It shows promise in inhibiting small cell lung carcinoma (SCLC) growth by altering DNA methylation.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Epigenetic dysregulation is a key driver in cancer development.
- Targeting epigenetic machinery offers a promising avenue for novel cancer therapies.
Purpose of the Study:
- To discover and characterize a novel inhibitor of Lysine Demethylase 1 (LSD1).
- To evaluate the efficacy of the LSD1 inhibitor GSK2879552 in various cancer types, particularly small cell lung carcinoma (SCLC).
Main Methods:
- Discovery and biological evaluation of GSK2879552, a cyclopropylamine-containing LSD1 inhibitor.
- In vitro proliferation screening of cancer cell lines.
- Assessment of DNA methylation patterns in response to LSD1 inhibition.
Main Results:
- GSK2879552 is identified as a potent, selective, orally bioavailable, and irreversible LSD1 inhibitor.
- Small cell lung carcinoma (SCLC) cell lines demonstrated sensitivity to LSD1 inhibition by GSK2879552.
- Growth inhibition in sensitive SCLC samples correlated with DNA hypomethylation, indicating a potential predictive biomarker.
Conclusions:
- GSK2879552 represents a potential targeted therapy for SCLC by inhibiting LSD1.
- DNA hypomethylation may serve as a predictive biomarker for patient response to LSD1 inhibition therapy.
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