Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax
Lee-Or Herzog 1, Beth Walters 2, Roberta Buono 1, J Scott Lee 1 3, Sharmila Mallya 1, Amos Fung 1, Honyin Chiu 1 4, Nancy Nguyen 1, Boyang Li 1, Anthony B Pinkerton 5, Michael R Jackson 5, Robert J Schneider 2, Ze’ev A Ronai 5, David A Fruman 6
Background: The BCL2 inhibitor venetoclax has proven effectiveness in a number of hematologic malignancies, using the finest response rates in indolent bloodstream cancers for example chronic lymphocytic leukaemia. There’s a lesser response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).
Methods: We tested inhibitors of cap-dependent mRNA translation for the opportunity 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 substance targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffold protein within the eIF4F complex.
Results: Management of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, that has been enhanced venetoclax effectiveness in vivo. SBI-756 avoided eIF4E-eIF4G1 association and cap-dependent translation without having affected mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells missing eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, resulting in a decrease in protein synthesis rates in sensitive cells. When normal lymphocytes were given SBI-756, only B cells had reduced viability, which correlated with reduced protein synthesis.
Conclusions: Our data highlight a singular combination to treat aggressive lymphomas, and establishes its effectiveness and selectivity using preclinical models.SBI-0640756