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|Ref Type||Journal Article|
|Authors||Lopez-Sambrooks C, Shrimal S, Khodier C, Flaherty DP, Rinis N, Charest JC, Gao N, Zhao P, Wells L, Lewis TA, Lehrman MA, Gilmore R, Golden JE, Contessa JN|
|Title||Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells.|
|Journal||Nature chemical biology|
|Abstract Text||Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|NGI-1||ML414||NGI-1 inhibits the activity of oligosacchyltransferase, which results in reduced N-linked glycosylation and may lead to decreased proliferation of tumor cells with dependence on receptor tyrosine kinase signaling (PMID: 27694802, PMID: 31511384).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR1 amp||lung non-small cell carcinoma||predicted - sensitive||NGI-1||Preclinical - Cell culture||Actionable||In a preclinical study, NGI-1 inhibited FGFR1 phosphorylation and proliferation of a FGFR1-amplified cell line dependent on FGFR1 signaling in culture, however, did not inhibit proliferation of an FGFR1-amplified cell line not dependent on FGFR1 signaling (PMID: 27694802).||27694802|