Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas

Xuan Zhang, Chengfeng Bi, Ting Lu, Weiwei Zhang, Ting Yue, Cheng Wang, Tian Tian, Xiaoyan Zhang, Yuhua Huang, Matthew A Lunning, Xinbao Hao, Lauren E. Brown, William G. Devine, Julie Marie Vose, John A. Porco, Kai Fu

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalLeukemia
DOIs
StatePublished - Jan 1 2019

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Lymphoma
Oncogene Proteins
Aurora Kinase A
Neoplasms
Disease Resistance
B-Cell Lymphoma
Proteome
Heterografts
Disease Progression
Cell Survival
Transcription Factors
Cell Proliferation
Drug Therapy
Survival
Growth
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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 A; Hao, Xinbao; Brown, Lauren E.; Devine, William G.; Vose, Julie Marie; Porco, John A.; Fu, Kai.

In: Leukemia, 01.01.2019.

Research output: Contribution to journalArticle

Zhang, X, Bi, C, Lu, T, Zhang, W, Yue, T, Wang, C, Tian, T, Zhang, X, Huang, Y, Lunning, MA, Hao, X, Brown, LE, Devine, WG, Vose, JM, Porco, JA & Fu, K 2019, 'Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas', Leukemia. https://doi.org/10.1038/s41375-019-0503-z
Zhang, Xuan ; Bi, Chengfeng ; Lu, Ting ; Zhang, Weiwei ; Yue, Ting ; Wang, Cheng ; Tian, Tian ; Zhang, Xiaoyan ; Huang, Yuhua ; Lunning, Matthew A ; Hao, Xinbao ; Brown, Lauren E. ; Devine, William G. ; Vose, Julie Marie ; Porco, John A. ; Fu, Kai. / Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas. In: Leukemia. 2019.
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abstract = "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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