Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax

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.

Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex

“…Only one of these, SBI-1232, potently inhibited OC43 transcripts and proteins in both Vero E6 and A549 cells, with minimal effects on cell viability. A positive control for our initial analyses was SBI-756, a small molecule eIF4F inhibitor that primarily targets eIF4G1 and is reportedly effective against several cancers ( Feng et al, 2015 ; Herzog et al, 2021 ). However, given the toxicity of SBI-756, we performed additional assessments of less toxic SBI-1232 and of structurally similar compounds that show enhanced potency for inhibition of OC43 RNA and protein production.…”

First Report of FARSA in the Regulation of Cell Cycle and Survival in Mantle Cell Lymphoma Cells via PI3K-AKT and FOXO1-RAG1 Axes

“…It is of interest to note that multiple cancer-related genes were also significantly increased in FARSA KD Jeko cells, including activating transcription factor 5 ( ATF5 ), eukaryotic translation initiation factor 4 gamma 1 ( EIF4G1 ), telomerase reverse transcriptase ( TERT ), KRAS proto-oncogene ( KRAS ), mitogen-activated protein kinase (MAPK) kinase 1 ( MAP2K1 ) and MAPK1 , which are key regulators contributing to the development and progression of MCL and other NHLs [ 12 , 13 , 23 , 24 , 25 ] ( Supplementary Figure S2 ). This finding suggests that other mechanisms may be simultaneously involved in FARSA-mediated pathogenesis and progression of MCL in addition to cell cycle.…”

Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation

“…37,38 Furthermore, we have previously shown that macrophages affect MCL-1 translation in CLL cells via the eIF4E-axis 40 and others reported that inhibition of eIF4F assembly in diffuse large B-cell lymphoma cells diminishes MCL-1 levels and synergizes with venetoclax. 41 In the pre-B ALL cell line NALM6, silmitasertib treatment was reported to enhance proteasomal degradation of MCL-1. 42 However, similar to our findings in MCL, in HEK cells Gandin et al 49 also observed that CK2 controls 4EBP phosphorylation and eIF4F complex assembly.…”

“…The rate of MCL-1 translation is amongst others dependent upon the eukaryotic translation initiation factor 4F (eIF4F) complex. [37][38][39][40][41] Association of this complex with mRNA depends on the cap-binding factor eIF4E, which is inhibited by eIF4E-binding protein (4EBP).…”