Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas
| العنوان: | Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas |
|---|---|
| المؤلفون: | John A. Porco, Yuhua Huang, Xuan Zhang, Lauren E. Brown, Kai Fu, Julie M. Vose, Ting Yue, Cheng Wang, Xinbao Hao, Tian Tian, Ting Lu, William G. Devine, Xiaoyan Zhang, Chengfeng Bi, Weiwei Zhang, Matthew A. Lunning |
| المصدر: | Leukemia |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Cancer Research, Lymphoma, B-Cell, (-)-SDS-1-021, Biology, translation initiation, PLK1, Article, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, 0302 clinical medicine, Eukaryotic translation, Downregulation and upregulation, rocaglate, medicine, Protein biosynthesis, Animals, Humans, MCL1, Peptide Chain Initiation, Translational, Transcription factor, Plant Extracts, MYC-driven lymphoma, double hit lymphoma, Hematology, medicine.disease, Antineoplastic Agents, Phytogenic, Xenograft Model Antitumor Assays, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, eIF4A, Cancer research, Female, Aglaia |
| الوصف: | 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. |
| تدمد: | 1476-5551 0887-6924 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::56c2e588a29b83ebf10be26fa3631214 https://doi.org/10.1038/s41375-019-0503-z |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....56c2e588a29b83ebf10be26fa3631214 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765551 08876924 |
|---|