LSD1 inhibition: a therapeutic strategy in cancer?

Abstract

Pre-clinical data supporting a therapeutic role for LSD1 inhibitors are most encouraging in acute myeloid leukaemia, although optimal dosing strategies and beneficial combinations with other agents remain unclear. Studies making use of potent, selective LSD1 inhibitors active in the nanomolar range are required to establish therapeutic indications in other subtypes of haematological malignancy, and in solid tumours.

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC

“…Aside from NCI-H1417, the only line displaying evidence of cytotoxicity, there was no obvious accumulation of cells in sub-G2 and there were no apparent changes in caspase-3 or PARP cleavage, indicating that the majority of cell lines did not undergo a cytotoxic response to GSK2879552 (Figures S2C-S2E; Table S3). This largely cytostatic profile is consistent with a pro-differentiation mechanism as previously reported for LSD1 inhibition in AML Lynch et al, 2012).…”

“…Lysine demethylase 1 (LSD1) is a histone modifying enzyme responsible for demethylating histone H3 lysine 4 (H3K4). LSD1 is overexpressed in many human cancers including lung, breast, prostate, and blood (Serce et al, 2012;Kahl et al, 2006;reviewed in Lim et al, 2010;Lynch et al, 2012;Lv et al, 2012). Studies involving knock down of LSD1 have suggested that loss of LSD1 expression reduces the growth of cancer cells as well as their potential for migration and invasion (Lv et al, 2012).…”

Chromatin proteins and modifications as drug targets

“…3c) 56 . Several data have suggested that LSD1 could be an interesting therapeutic target in cancer, because of its high--level expression in prostate cancer, undifferentiated neuroblastoma, oestrogen--negative breast cancer, bladder cancer and colorectal cancer 57--60 .…”

Compartmentation of Metabolites in Regulating Epigenomes of Cancer

“…LSD1 overexpression is associated with several cancer cell lines and some types of tumors. It has become an attractive target for cancer therapy (74,132). So a possible role of riboflavin, the precursor of FAD, in cancer was also tested in few studies, In breast, liver, colon, lung and prostate cancers, cytoplasmic acetyl-CoA may be produced mainly through ACL-mediated citrate-to-acetyl-CoA conversion.…”