Targeting N-myristoylation for therapy of B-cell lymphomas

Nat Commun. 2020 Oct 22;11(1):5348. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dasatinib / pharmacology
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Mice
  • Mice, SCID
  • Models, Biological
  • Myristic Acid / metabolism*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / metabolism

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • DDD 85646
  • Enzyme Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • Sulfonamides
  • Myristic Acid
  • ibrutinib
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase
  • src-Family Kinases
  • Dasatinib