Browse
Submit Data
Databases
API
Help

Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

32 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (ChIP-Seq)

ABSTRACT: Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new 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 inhibitor 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. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To investigate the mechanism of LSD1 efficacy in SCLC cell lines we used chromatin immunoprecipitation (ChIP) sequencing studies to examine the genomic distribution of LSD1 as well as H3K4me2 and H3K4me1 in NCI-H526 SCLC cells in the absence and presence of LSD1 inhibition.

ORGANISM(S): Homo sapiens

SUBMITTER: David Soong

PROVIDER: E-GEOD-66297 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Json Xml

Similar Datasets

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (microarray)

Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new 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 inhibitor 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. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. To gain insight into the mechanism of LSD1 inhibition in inhibiting growth in SCLC cell lines, the effect of GSK2879552 on gene expression was evaluated in 6 SCLC lines, three sensitive to the growth inhibitory effects of GSK2879552 and three resistant. Expression was measured on Affy HG-U133_PLUS_2 microarrays at three time points (2, 4, and 7 days) with replicates.

2015-07-14 | E-GEOD-66294 | biostudies-arrayexpress

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (BeadChip)

Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new 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 inhibitor 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. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. DNA methylation profiling was performed using Infinium 450K methylation arrays on SCLC cell lines, patient derived xenografts, and patient samples. Data was processed and normalized using GenomeStudio V2011.1

2015-07-14 | E-GEOD-66295 | biostudies-arrayexpress

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (microarray)

2015-07-14 | GSE66294 | GEO

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (ChIP-Seq)

2015-07-14 | GSE66297 | GEO

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC (BeadChip)

2015-07-14 | GSE66295 | GEO

Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing

Project description:The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically “cold” tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with A) decreased neuroendocrine characteristics and B) activation of NOTCH signaling. We previously showed that inhibition of the LSD1 demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD1 inhibition in SCLC.

2022-08-17 | GSE208614 | GEO

LSD1 inhibitor T-3775440 inhibits SCLC cell proliferation by disrupting LSD1 interactions with SNAG domain proteins INSM1 and GFI1B

Project description:T-3775440 is an irreversible inhibitor of the chromatin demethylase LSD1. Here we describe the anti-cancer effects and mechanism of action of T-3775440 in small cell lung cancer (SCLC). T-3775440 inhibited proliferation of SCLC cells in vitro and retarded SCLC tumor growth in vivo. Our results argue that LSD1 plays an important role in neuroendocrine-associated transcription and cell proliferation of SCLC via interactions with the SNAG domain proteins INSM1 and GFI1B. Targeting these critical interactions with LSD1 inhibitors offers a novel rational strategy to therapeutically manage SCLC.

2018-02-01 | GSE100169 | GEO

Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer

Project description:A subset of small cell lung cancer (SCLC) shows a clinical response to PARP inhibitors (PARPi) despite being proficient in homologous repair pathways. However, the underlying mechanism(s) of PARPi sensitivity is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in a large panel of molecularly annotated patient-derived SCLC lines. We found that the toxicity of PARPi in SCLC is explained by the PARPi-induced degradation of key lineage-specific oncoproteins including ASCL1, NEUROD1, POU2F3, KDM4A, and KDM5B. Biochemical experiments showed that PARPi-induced activation of E3 ligases (e.g., HUWE1 and RNF8) mediated the ubiquitin-proteasome system (UPS)-dependent degradation of these oncoproteins. Interestingly, although PARPi resulted in a general DNA damage response, this signal is sensed by different SCLC cell lines to generate a cell-specific response. The dissection of the cell-specific oncoprotein degradation response led to the identification of potentially predictive biomarkers for PARPi in SCLC. The combination of PARPi and agents targeting these pathways led to dramatically improved cytotoxicity in SCLC. PARPi-induced degradation of lineage-specific oncoproteins therefore represents a novel mechanism to explain the efficacy of PARPi in tumors without homologous recombination deficiency.

2024-01-26 | PXD029972 | Pride

Induced Degradation of Lineage-specific Oncoproteins Underlies the Selective PARP1 Inhibitor Toxicity in Small Cell Lung Cancer (batch2-6)

2024-01-26 | PXD029968 | Pride

Comparison of 7 small cell lung cancer PDX models, cultured ex vivo, for response to LSD1 inhibitor RG6016/ORY1001

Project description:The goal of this study was to understand how the LSD1 inhibitor RG6016/ORY1001 leads to selective efficacy in subsets of small cell lung cancer. SCLC cell lines, PDX models studied ex vivo and studied in vivo were employed in this analysis

2019-06-10 | GSE103095 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data