MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition

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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

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Published on: July 20, 2019

Gregor A Lueg¹, James Zhang², Monica Faronato¹

¹Department of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.

|August 24, 2025

Abstract:

Human N-myristoyltransferases (NMTs) catalyze N-terminal protein N-myristoylation and are promising targets in cancer, with an emerging mechanistic rationale for targeted therapy. Here, we screened 245 cancer cell lines against IMP-1320, a potent NMT inhibitor (NMTi), and conducted pathway-level analyses to identify that deregulated MYC increases cancer cell sensitivity to NMTis. Proteomics on detergent-enriched membrane fractions in MYC or MYCN-deregulated cancer cell models revealed that cell death is associated at least in part with loss of membrane association of mitochondrial respiratory complex I. This is concurrent with loss of myristoylation and degradation of the complex I assembly factor NDUFAF4, and induction of mitochondrial dysfunction, driven by MYC or MYCN-deregulation. NMTis eliminated or suppressed MYC- and MYCN-driven tumors in vivo without overt toxicity, suggesting that this constitutive co-translational protein modification can be targeted in MYC-driven cancers.

Insights

Human N-myristoyltransferases (NMTs) are cancer targets. Inhibiting NMTs with IMP-1320 shows MYC-driven cancers are sensitive, leading to mitochondrial dysfunction and tumor suppression without toxicity.

Area of Science:

Biochemistry
Molecular Biology
Oncology

Background:

Human N-myristoyltransferases (NMTs) catalyze protein N-myristoylation.
NMTs are emerging targets for cancer therapy.
MYC deregulation is implicated in various cancers.

Purpose of the Study:

To screen NMT inhibitors (NMTis) across cancer cell lines.
To identify mechanisms linking MYC deregulation to NMTi sensitivity.
To evaluate NMTis as a therapeutic strategy for MYC-driven cancers.

Main Methods:

Screening 245 cancer cell lines with NMT inhibitor IMP-1320.
Pathway-level analyses to assess MYC-deregulation impact.
Proteomics on membrane fractions from MYC/MYCN-deregulated cells.
In vivo tumor suppression studies.

Main Results:

Deregulated MYC enhances cancer cell sensitivity to NMTis.
NMT inhibition leads to loss of mitochondrial respiratory complex I membrane association.
This is linked to NDUFAF4 degradation and mitochondrial dysfunction.
NMTis suppressed MYC/MYCN-driven tumors in vivo with minimal toxicity.

Conclusions:

NMT inhibition is a viable therapeutic strategy for MYC-driven cancers.
Targeting N-myristoylation offers a novel approach to cancer treatment.
MYC/MYCN deregulation confers sensitivity to NMT inhibitors.

Read full analysis

Keywords:

CP: Cancer CP: Molecular biology Complex I MYC MYCN N-myristoylation N-myristoyltransferase NDUFAF4 NMT

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