# OST Inhibition in NSCLC

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $463,580

## Abstract

Non-small cell lung cancers (NSCLC) are aggressive tumors that are a major cause of morbidity and mortality
in the United States. In the past decade, the introduction of systemic therapies such as receptor tyrosine
kinase targeted inhibitors and immune checkpoint inhibitors have significantly improved patient outcomes.
However, therapeutic resistance to these therapies frequently develops and is characterized by parallel
signaling through other co-expressed receptor glycoproteins. We have therefore investigated the feasibility of
disrupting asparagine (N) linked glycosylation, a co- and post-translational protein modification, as a strategy
to block both primary and bypass glycoprotein survival signaling in NSCLC. Although this pathway is target
rich and involves at least 34 gene products, pharmacologic inhibitors that regulate this process have not
previously been available. We have identified a first in class small molecule inhibitor of the
oligosaccharyltransferase (OST), the multi-subunit enzymatic complex that transfers glycans to elongating
proteins in the endoplasmic reticulum. This inhibitor reduces OST fidelity by targeting the catalytic subunit and
results in a site-specific and partial inhibition of glycosylation. In NSCLC with activation of RTK dependent
oncogenic signaling, OST inhibition blocks tumor cell proliferation and couples favorably with TKIs to enhance
apoptosis and xenograft tumor growth. We now propose to characterize and advance novel small molecule
inhibitors of the OST with respect to catalytic subunit inhibition and effects on EGFR driven NSCLC. Because
glycoprotein bypass signaling is also operative in NSCLC subtypes with FGFR1 amplification or KRAS
mutation, we will define the signaling mechanisms and determine the sensitivity of these tumors to OST
inhibition. This project will also investigate the effects of OST inhibition on NSCLC radiosensitivity and identify
how glycoprotein dependent cellular programs mediate intrinsic and immune mediated therapeutic resistance.
Together this work will advance OST inhibition as a novel treatment strategy for NSCLC with the potential of
delivering an OST inhibitor that can be translated to the clinic.

## Key facts

- **NIH application ID:** 10853041
- **Project number:** 5R01CA240418-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Joseph N Contessa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,580
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853041

## Citation

> US National Institutes of Health, RePORTER application 10853041, OST Inhibition in NSCLC (5R01CA240418-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10853041. Licensed CC0.

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