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; Luc G. Berthiaume

doi:10.1038/s41467-020-18998-1

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, Luc G. Berthiaume (Lead / Corresponding author)

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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.

Original language	English
Article number	5348
Number of pages	16
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-18998-1
Publication status	Published - 22 Oct 2020

Keywords

B-cell lymphoma
Cell signaling
Target identification

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Beauchamp, E., Yap, M. C., Iyer, A., Perinpanayagam, M. A., Gamma, J. M., Vincent, K. M., Lakshmanan, M., Raju, A., Tergaonkar, V., Tan, S. Y., Lim, S. T., Dong, W.-F., Postovit, L. M., Read, K. D., Gray, D. W., Wyatt, P. G., Mackey, J. R., & Berthiaume, L. G. (2020). Targeting N-myristoylation for therapy of B-cell lymphomas. Nature Communications, 11, Article 5348. https://doi.org/10.1038/s41467-020-18998-1

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title = "Targeting N-myristoylation for therapy of B-cell lymphomas",

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.",

keywords = "B-cell lymphoma, Cell signaling, Target identification",

author = "Erwan Beauchamp and Yap, {Megan C.} and Aishwarya Iyer and Perinpanayagam, {Maneka A.} and Gamma, {Jay M.} and Vincent, {Krista M.} and Manikandan Lakshmanan and Anandhkumar Raju and Vinay Tergaonkar and Tan, {Soo Yong} and Lim, {Soon Thye} and Wei-Feng Dong and Postovit, {Lynne M.} and Read, {Kevin D.} and Gray, {David W.} and Wyatt, {Paul G.} and Mackey, {John R.} and Berthiaume, {Luc G.}",

note = "Funding Information: We thank Cheryl Santos for technical assistance. We thank Drs. Deanna Hockley, Larissa Vos, and Joseph Brandwein for their input and editing of the manuscript. We thank Dr. Marek Michalak (University of Alberta) for discussions and conceptual assistance with calcium measurements and Dr. J. Dillberger for analysis and interpretations of toxicology data. We sincerely thank Drs. Ong Choon Kiat and Dachuan Huang for providing us with the DLBCL3 PDX samples, which were used for the efficacy evaluation of PCLX-001. This work was supported by Alberta Cancer Foundation (ACF) grants 26362 and 26927, the Mary Agnes & Ivan Radostits ACF donor directed grant 26380 to LGB, by Eusera (www.eusera.com) and Pacylex Pharmaceuticals Inc. (www.pacylex.com) as well as an Alberta Innovates Translational Health Chair held by L.M.P. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = oct,

day = "22",

doi = "10.1038/s41467-020-18998-1",

language = "English",

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journal = "Nature Communications",

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AU - Beauchamp, Erwan

AU - Yap, Megan C.

AU - Iyer, Aishwarya

AU - Perinpanayagam, Maneka A.

AU - Gamma, Jay M.

AU - Vincent, Krista M.

AU - Lakshmanan, Manikandan

AU - Raju, Anandhkumar

AU - Tergaonkar, Vinay

AU - Tan, Soo Yong

AU - Lim, Soon Thye

AU - Dong, Wei-Feng

AU - Postovit, Lynne M.

AU - Read, Kevin D.

AU - Gray, David W.

AU - Wyatt, Paul G.

AU - Mackey, John R.

AU - Berthiaume, Luc G.

N1 - Funding Information: We thank Cheryl Santos for technical assistance. We thank Drs. Deanna Hockley, Larissa Vos, and Joseph Brandwein for their input and editing of the manuscript. We thank Dr. Marek Michalak (University of Alberta) for discussions and conceptual assistance with calcium measurements and Dr. J. Dillberger for analysis and interpretations of toxicology data. We sincerely thank Drs. Ong Choon Kiat and Dachuan Huang for providing us with the DLBCL3 PDX samples, which were used for the efficacy evaluation of PCLX-001. This work was supported by Alberta Cancer Foundation (ACF) grants 26362 and 26927, the Mary Agnes & Ivan Radostits ACF donor directed grant 26380 to LGB, by Eusera (www.eusera.com) and Pacylex Pharmaceuticals Inc. (www.pacylex.com) as well as an Alberta Innovates Translational Health Chair held by L.M.P. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/10/22

Y1 - 2020/10/22

N2 - 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.

AB - 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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KW - Cell signaling

KW - Target identification

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DO - 10.1038/s41467-020-18998-1

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JO - Nature Communications

JF - Nature Communications

M1 - 5348

ER -

Targeting N-myristoylation for therapy of B-cell lymphomas

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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