Lymphoma

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

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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Acknowledgements

We would like to thank Jerry Pelletier at the McGill University for his valuable advice and comments to the paper. We thank Joseph Gera (Greater Los Angeles VA Healthcare System, CA, USA) for providing us the pRF plasmid. We thank Dirk Eick (Helmholtz Zentrum München, Munich, Germany) for providing us P493-6 cell line. We thank John Chan (City of Hope, CA, USA) for providing NKYS cell line. We thank Richard J. Ford (MD. Anderson, TX, USA) for providing CJ cell line. We thank Sophie Alvarez and Michael Naldrett at the Proteomics and Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska-Lincoln, supported by the Nebraska Research Initiative for performing the proteomics analysis. We sincerely thank Wang Yuzhuo (Vancouver, British Columbia) at the Living Tumor Laboratory for providing the MYC/BCL2 double expression PDX model. We thank David M. Weinstock and Dana-Farber’s bank of patient-derived tumor xenografts (Dana-Farber Cancer Institute, MA, USA) for providing the MYC/BCL2 double-translocation PDX line.

Funding

This study was supported in part by a pilot grant and a lymphoma program grant from the Fred & Pamela Buffett Cancer Center at UNMC (to KF), the National Cancer Institute (P30 CA036727), Nebraska Department of Health and Human Services (LB506-18-22 to KF), and the National Institutes of Health (R35 GM118173 and R24 GM111625 to JAP, Jr).

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Correspondence to Kai Fu.

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Zhang, X., Bi, C., Lu, T. et al. Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas. Leukemia 34, 138–150 (2020). https://doi.org/10.1038/s41375-019-0503-z

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