DNA 低甲基化特征可预测 LSD1 抑制剂在 SCLC 中的抗肿瘤活性。
A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC.
机构信息
Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.
Oncology Department, Johns Hopkins University, Baltimore, MD 21231, USA.
出版信息
Cancer Cell. 2015 Jul 13;28(1):57-69. doi: 10.1016/j.ccell.2015.06.002.
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.
表观遗传失调已成为癌症的一个重要机制。表观遗传机制的改变已成为靶向治疗的主要焦点。本报告描述了含有环丙胺的赖氨酸去甲基酶 1（LSD1）抑制剂的发现和生物学活性。这种小分子是一种有效的、选择性的、口服生物利用的、基于机制的 LSD1 不可逆失活剂。对代表多种肿瘤类型的细胞系进行的增殖筛选表明，小细胞肺癌（SCLC）对 LSD1 抑制敏感。对 LSD1 抑制剂 GSK2879552 有反应的 SCLC 系和原发性样本亚组表现出一组特征探针的 DNA 低甲基化，这表明这可能被用作活性的预测生物标志物。
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