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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783476577010450432 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6895415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT zhangxuan targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT bichengfeng targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT luting targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT zhangweiwei targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT yueting targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT wangcheng targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT tiantian targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT zhangxiaoyan targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT huangyuhua targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT lunningmatthew targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT haoxinbao targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT brownlaurene targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT devinewilliamg targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT vosejulie targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT porcojohna targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas AT fukai targetingtranslationinitiationbysyntheticrocaglatesfortreatingmycdrivenlymphomas |