Reference Detail

Ref Type

Journal Article

PMID

(27694802)

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	Vol	Issue	Date	Pages	Journal Short Title
Nature chemical biology	12	12	2016 Dec	1023-1030	Nat Chem Biol

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
NGI-1	NGI-1	1	0

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