MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition
Summary: 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-...
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Elsevier
2025-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725009519 |
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| author | Gregor A. Lueg James Zhang Monica Faronato Andrii Gorelik Wouter W. Kallemeijn Francesco Falciani Josephine Walton Jack W. Houghton Silvia Vannini Evon Poon Barbara M. Costa Roberto Solari Robin Carr Andrew S. Bell Edward J. Bartlett Bernadette Brzezicha Martin Janz Louis Chesler Dinis P. Calado Edward W. Tate |
| author_facet | Gregor A. Lueg James Zhang Monica Faronato Andrii Gorelik Wouter W. Kallemeijn Francesco Falciani Josephine Walton Jack W. Houghton Silvia Vannini Evon Poon Barbara M. Costa Roberto Solari Robin Carr Andrew S. Bell Edward J. Bartlett Bernadette Brzezicha Martin Janz Louis Chesler Dinis P. Calado Edward W. Tate |
| author_sort | Gregor A. Lueg |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-ecd08d7f5cdd4c28a20917c61c386063 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-ecd08d7f5cdd4c28a20917c61c3860632025-08-24T05:12:07ZengElsevierCell Reports2211-12472025-09-0144911618010.1016/j.celrep.2025.116180MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibitionGregor A. Lueg0James Zhang1Monica Faronato2Andrii Gorelik3Wouter W. Kallemeijn4Francesco Falciani5Josephine Walton6Jack W. Houghton7Silvia Vannini8Evon Poon9Barbara M. Costa10Roberto Solari11Robin Carr12Andrew S. Bell13Edward J. Bartlett14Bernadette Brzezicha15Martin Janz16Louis Chesler17Dinis P. Calado18Edward W. Tate19Department 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, UKDepartment 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; Division of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UKDepartment 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, UKDepartment 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, UKDepartment 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, UKMyricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UKDepartment of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UKDepartment of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UKDepartment of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UKDivision of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UKDivision of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UKMyricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UKMyricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UKDepartment of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UK; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UKDepartment of Chemistry, Molecular Sciences Research Hub, White City Campus, Imperial College London, 82 Wood Lane, W12 0BZ London, UKExperimental Pharmacology & Oncology Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, GermanyExperimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité – Universitätsmedizin Berlin, 13125 Berlin, GermanyDivision of Clinical Studies, The Institute of Cancer Research (ICR) & Royal Marsden NHS Trust, SW3 6JB London, UKThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK; Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London, The Francis Crick, SE1 9RT London, UK; Corresponding authorDepartment 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; Myricx Pharma Limited, London Innovation Centre, 20 Water Street, E14 5GX London, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725009519CP: CancerCP: Molecular biology |
| spellingShingle | Gregor A. Lueg James Zhang Monica Faronato Andrii Gorelik Wouter W. Kallemeijn Francesco Falciani Josephine Walton Jack W. Houghton Silvia Vannini Evon Poon Barbara M. Costa Roberto Solari Robin Carr Andrew S. Bell Edward J. Bartlett Bernadette Brzezicha Martin Janz Louis Chesler Dinis P. Calado Edward W. Tate MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition Cell Reports CP: Cancer CP: Molecular biology |
| title | MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition |
| title_full | MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition |
| title_fullStr | MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition |
| title_full_unstemmed | MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition |
| title_short | MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition |
| title_sort | myc deregulation sensitizes cancer cells to n myristoyltransferase inhibition |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725009519 |
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