MYC deregulation sensitizes cancer cells to N-myristoyltransferase inhibition
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.
Authors
- Edward W. Tate (ORCID: https://orcid.org/0000-0003-2213-5814)
- Monica Faronato
- James Zhang (ORCID: https://orcid.org/0000-0002-6251-0474)
- Josephine Walton
- Wouter W. Kallemeijn (ORCID: https://orcid.org/0000-0002-3660-2930)
- Edward J. Bartlett
- Roberto Solari (ORCID: https://orcid.org/0000-0002-7660-3460)
- Samuele Vannini (ORCID: https://orcid.org/0000-0002-9940-4544)
- Dinis Pedro Calado (ORCID: https://orcid.org/0000-0001-8239-7184)
- Robin A. E. Carr
- Barbara Martins Da Costa (ORCID: https://orcid.org/0000-0002-8993-6790)
- Martin Janz (ORCID: https://orcid.org/0000-0002-1127-0044)
- Jack W. Houghton (ORCID: https://orcid.org/0000-0002-2971-0271)
- Louis Chesler (ORCID: https://orcid.org/0000-0001-7842-2068)
- Evon Poon (ORCID: https://orcid.org/0000-0002-0616-2487)
- Andrii Gorelik (ORCID: https://orcid.org/0000-0001-5354-4042)
- Gregor A. Lueg
- Francesco Falciani (ORCID: https://orcid.org/0000-0003-1432-2871)
- Bernadette Brzezicha
- Andrew Bell (ORCID: https://orcid.org/0000-0002-0581-9387)
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Max Delbrück Center (DE)
- The Francis Crick Institute (GB)
- London Biofoundry (GB)
- Redx Pharma (United Kingdom) (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1016/j.celrep.2025.116180
- Citations
- 2
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- University of Pennsylvania
- Ludwig Institute for Cancer Research
- Wellcome Trust
- Francis Crick Institute
- Cancer Research UK
- Imperial College London
- Deutsche Forschungsgemeinschaft
- Medicines for Malaria Venture
- Medical Research Council
- Engineering and Physical Sciences Research Council