Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax
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Published:2020-12-14
Issue:6
Volume:124
Page:1098-1109
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ISSN:0007-0920
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Container-title:British Journal of Cancer
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language:en
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Short-container-title:Br J Cancer
Author:
Herzog Lee-or, Walters Beth, Buono Roberta, Lee J. Scott, Mallya Sharmila, Fung Amos, Chiu Honyin, Nguyen Nancy, Li Boyang, Pinkerton Anthony B., Jackson Michael R., Schneider Robert J., Ronai Ze’ev A.ORCID, Fruman David A.ORCID
Abstract
Abstract
Background
The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).
Methods
We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex.
Results
Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis.
Conclusions
Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.
Funder
U.S. Department of Health & Human Services | National Institutes of Health U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health Breast Cancer Research Fund BCRF-16-143
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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