Expression profiling of the effect of treatment with GNF-7 on mutant NRAS-positive leukemia cell lines

ABSTRACT: The complexity of RAS signaling makes targeting RAS challenging. We therefore hypothesized that inhibiting a combination of downstream targets of RAS may potentially lead to an effective therapeutic intervention. We performed a high-throughput chemical screen using a library consisting of multi-targeted inhibitors with the expectation that one or more inhibitors would likely- due to their broad spectrum inhibitory potential- hit critical targets of mutant NRAS. We identified GNF-7, a multi-targeted kinase inhibitor that proved to have high selectivity and sensitivity for leukemia cells with NRAS mutations both in vitro and in vivo. We used microarrays to determine which transcripts were affected by treatment with GNF-7. We selected a single comparative timepoint, 8 hours post-treatment with GNF-7. GSEA (gene set enrichment analysis) was performed using gene signatures in MSigDB (Molecular Signatures Database) for analysis. This led to the identification of MYC-network genes as being the downstream conduit of the effect of this treatment. We also found that treatment with GNF-7 abolished

ORGANISM(S): Homo sapiens

PROVIDER: GSE49534 | GEO | 2015/12/01

SECONDARY ACCESSION(S): PRJNA214191

REPOSITORIES: GEO