Targeting N-myristoylation for therapy of B-cell lymphomas

Erwan Beauchamp, Megan C. Yap, Aishwarya Iyer, Maneka A. Perinpanayagam, Jay M. Gamma, Krista M. Vincent, Manikandan Lakshmanan, Anandhkumar Raju, Vinay Tergaonkar, Soo Yong Tan, Soon Thye Lim, Wei-Feng Dong, Lynne M. Postovit, Kevin D. Read, David W. Gray, Paul G. Wyatt, John R. Mackey and Luc G. Berthiaume ()
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Erwan Beauchamp: University of Alberta
Megan C. Yap: University of Alberta
Aishwarya Iyer: University of Alberta
Maneka A. Perinpanayagam: University of Alberta
Jay M. Gamma: University of Alberta
Krista M. Vincent: University of Alberta
Manikandan Lakshmanan: Institute of Molecular and Cell Biology
Anandhkumar Raju: Institute of Molecular and Cell Biology
Vinay Tergaonkar: Institute of Molecular and Cell Biology
Soo Yong Tan: Institute of Molecular and Cell Biology
Soon Thye Lim: National Cancer Centre Singapore
Wei-Feng Dong: University of Alberta
Lynne M. Postovit: University of Alberta
Kevin D. Read: University of Dundee, James Black Centre
David W. Gray: University of Dundee, James Black Centre
Paul G. Wyatt: University of Dundee, James Black Centre
John R. Mackey: Pacylex Pharmaceuticals Inc.
Luc G. Berthiaume: University of Alberta

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18998-1

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