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Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.
Beauchamp, Erwan; Gamma, Jay M; Cromwell, Christopher R; Moussa, Eman W; Pain, Rony; Kostiuk, Morris A; Acevedo-Morantes, Claudia; Iyer, Aishwarya; Yap, Megan; Vincent, Krista M; Postovit, Lynne M; Julien, Olivier; Hubbard, Basil P; Mackey, John R; Berthiaume, Luc G.
Afiliación
  • Beauchamp E; Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada.
  • Gamma JM; Department of Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Cromwell CR; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Moussa EW; Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Pain R; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Kostiuk MA; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Acevedo-Morantes C; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Iyer A; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Yap M; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Vincent KM; Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Postovit LM; Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Julien O; Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Hubbard BP; Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
  • Mackey JR; Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada.
  • Berthiaume LG; Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada. luc.berthiaume@ualberta.ca.
J Transl Med ; 22(1): 431, 2024 May 07.
Article en En | MEDLINE | ID: mdl-38715059
ABSTRACT

BACKGROUND:

In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. METHODS AND

RESULTS:

Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.

CONCLUSIONS:

Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Aciltransferasas / Neoplasias Límite: Humans Idioma: En Revista: J Transl Med Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosforilación Oxidativa / Aciltransferasas / Neoplasias Límite: Humans Idioma: En Revista: J Transl Med Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido