Targeting N-myristoylation for therapy of B-cell lymphomas

  • Nat Commun. 2020 Oct 22;11(1):5348. doi: 10.1038/s41467-020-18998-1.
Erwan Beauchamp  1  2 ,  Megan C Yap  1  2 ,  Aishwarya Iyer  1 ,  Maneka A Perinpanayagam  1  2 ,  Jay M Gamma  3 ,  Krista M Vincent  4 ,  Manikandan Lakshmanan  5 ,  Anandhkumar Raju  6  7 ,  Vinay Tergaonkar  6  7 ,  Soo Yong Tan  6  7 ,  Soon Thye Lim  8 ,  Wei-Feng Dong  4 ,  Lynne M Postovit  4 ,  Kevin D Read  9 ,  David W Gray  9 ,  Paul G Wyatt  9 ,  John R Mackey  2  4 ,  Luc G Berthiaume  10  11
Affiliations
  • 1. Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada.
  • 2. Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada.
  • 3. Departments of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada.
  • 4. Departments of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada.
  • 5. Mouse Models of Human Cancer Unit, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore.
  • 6. Advanced Molecular Pathology Lab, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore, 138673.
  • 7. Department of Pathology, National University of Singapore, Singapore, Singapore.
  • 8. Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Outram Road, Singapore, 169610, Singapore.
  • 9. Drug Discovery Unit, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
  • 10. Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, T6G 2H7, AB, Canada. [email protected].
  • 11. Pacylex Pharmaceuticals Inc., Edmonton, AB, Canada. [email protected].
PMID: 33093447 DOI: 10.1038/s41467-020-18998-1
Abstract

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because Cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic Cancer cell line screens and discovered a marked sensitivity of hematological Cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to Cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.

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