Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein sy...

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Autores principales: Zhang, Xuan, Bi, Chengfeng, Lu, Ting, Zhang, Weiwei, Yue, Ting, Wang, Cheng, Tian, Tian, Zhang, Xiaoyan, Huang, Yuhua, Lunning, Matthew, Hao, Xinbao, Brown, Lauren E., Devine, William G., Vose, Julie, Porco, John A., Fu, Kai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895415/
https://www.ncbi.nlm.nih.gov/pubmed/31171817
http://dx.doi.org/10.1038/s41375-019-0503-z
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author Zhang, Xuan
Bi, Chengfeng
Lu, Ting
Zhang, Weiwei
Yue, Ting
Wang, Cheng
Tian, Tian
Zhang, Xiaoyan
Huang, Yuhua
Lunning, Matthew
Hao, Xinbao
Brown, Lauren E.
Devine, William G.
Vose, Julie
Porco, John A.
Fu, Kai
author_facet Zhang, Xuan
Bi, Chengfeng
Lu, Ting
Zhang, Weiwei
Yue, Ting
Wang, Cheng
Tian, Tian
Zhang, Xiaoyan
Huang, Yuhua
Lunning, Matthew
Hao, Xinbao
Brown, Lauren E.
Devine, William G.
Vose, Julie
Porco, John A.
Fu, Kai
author_sort Zhang, Xuan
collection PubMed
description MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (−)-SDS-1–021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.
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spelling pubmed-68954152019-12-21 Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas Zhang, Xuan Bi, Chengfeng Lu, Ting Zhang, Weiwei Yue, Ting Wang, Cheng Tian, Tian Zhang, Xiaoyan Huang, Yuhua Lunning, Matthew Hao, Xinbao Brown, Lauren E. Devine, William G. Vose, Julie Porco, John A. Fu, Kai Leukemia Article MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (−)-SDS-1–021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas. 2019-06-06 2020-01 /pmc/articles/PMC6895415/ /pubmed/31171817 http://dx.doi.org/10.1038/s41375-019-0503-z Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Zhang, Xuan
Bi, Chengfeng
Lu, Ting
Zhang, Weiwei
Yue, Ting
Wang, Cheng
Tian, Tian
Zhang, Xiaoyan
Huang, Yuhua
Lunning, Matthew
Hao, Xinbao
Brown, Lauren E.
Devine, William G.
Vose, Julie
Porco, John A.
Fu, Kai
Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas
title Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas
title_full Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas
title_fullStr Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas
title_full_unstemmed Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas
title_short Targeting Translation Initiation by Synthetic Rocaglates for Treating MYC-driven Lymphomas
title_sort targeting translation initiation by synthetic rocaglates for treating myc-driven lymphomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895415/
https://www.ncbi.nlm.nih.gov/pubmed/31171817
http://dx.doi.org/10.1038/s41375-019-0503-z
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