Hematology · 23 h ago
eIF4F inhibition sensitizes drug-resistant CML cells to TKIs in preclinical models
A preclinical study in Leukemia found that targeting the eIF4F translation initiation complex reduced BCR::ABL1 expression and sensitized resistant CML cells to tyrosine kinase inhibitors. Findings included activity in T315I-mutant cells and combination effects in a patient-derived xenograft model; sample sizes were not provided in the available preview.
- Activated eIF4F components were identified in imatinib-resistant CML cells.
- SBI-756 reduced BCR::ABL1 expression and impaired resistant stem/progenitor cell survival.
- TKI combinations showed reported synergy in vitro and xenografts.
- Clinical efficacy and safety remain unestablished.
Researchers investigated whether inhibiting protein translation could address tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). Using high-content antibody microarrays and bioinformatics, they examined proteomic and phosphorylation differences in imatinib-resistant cells. They identified activated components of the eIF4F translation initiation complex, particularly eIF4G1, with high expression and activation also observed in CD34-positive CML stem/progenitor cells.
Genetic inhibition of eIF4G1 or pharmacological targeting with SBI-756 disrupted eIF4F assembly, reduced overall translation initiation, and decreased BCR::ABL1 expression and key downstream targets. These interventions impaired survival of nonresponder stem/progenitor cells, including cells carrying the BCR::ABL1-T315I mutation. The authors reported strong synergistic effects with TKIs in vitro and in a patient-derived xenograft model.
The findings support further investigation of translation inhibition as a strategy against resistant CML, but do not establish clinical efficacy or safety. The available subscription preview provides no sample sizes, quantitative effect estimates, or detailed toxicity results, limiting assessment of robustness and therapeutic selectivity.
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Leukemia: Targeting the eIF4F translation initiation complex disrupts BCR::ABL1 translation and overcomes drug resistance in CML ↗This is an automated AI-condensed summary that has not yet been reviewed by an editor. Always consult the full item at the original source.