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

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.

 

Comments:

The study you mentioned investigated the potential of using inhibitors of cap-dependent mRNA translation in combination with the BCL2 inhibitor venetoclax to enhance its effectiveness in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

The researchers compared two inhibitors: MLN0128, an mTOR kinase inhibitor (TOR-KI), and SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), which is a scaffolding protein in the eIF4F complex involved in mRNA translation initiation.

The results showed that treatment with SBI-756 in combination with venetoclax led to increased apoptosis (cell death) in DLBCL and MCL cells both in vitro (in cell cultures) and in vivo (in animal models). SBI-756 achieved this by preventing the association between eIF4E and eIF4G1, thus inhibiting cap-dependent translation without affecting mTOR substrate phosphorylation.

Interestingly, even in TOR-KI-resistant DLBCL cells that lacked eIF4E binding protein-1, SBI-756 still sensitized the cells to venetoclax. SBI-756 selectively reduced the translation of specific mRNAs encoding ribosomal proteins and translation factors, resulting in reduced protein synthesis rates in sensitive cells.

Furthermore, when normal lymphocytes were treated with SBI-756, only B cells exhibited reduced viability, and this reduction correlated with decreased protein synthesis.

In conclusion, these findings suggest that the combination of SBI-756 and venetoclax may be a promising therapeutic strategy for aggressive lymphomas. The study provides preclinical evidence of the efficacy and selectivity of this combination in experimental models. However, further research and clinical trials are necessary to validate these findings and determine the potential for translation into clinical practice.

Related Products

Cat.No. Product Name Information
S8181 SBI-0640756 SBI-0640756(SBI-756) is a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. It can also suppress AKT and NF-κB signaling.

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eIF