Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax |
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Authors: | Lee-or Herzog Beth Walters Roberta Buono J Scott Lee Sharmila Mallya Amos Fung Honyin Chiu Nancy Nguyen Boyang Li Anthony B Pinkerton Michael R Jackson Robert J Schneider Zeev A Ronai David A Fruman |
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Institution: | 1.Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697 USA ;2.New York University School of Medicine, New York, NY USA ;3.Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037 USA ;4.Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121 USA ;5.Benaroya Research Institute, Seattle, WA 98101 USA |
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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.Subject terms: B-cell lymphoma, Molecular medicine |
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