Figure 1. Mechanism of action of eIF4E ASOs.

(A) In normal tissues, eIF4E is typically sequestered by hypophosphorylated 4E-BPs, resulting in restricted translation rates. Homeostasis is maintained by limiting translation to essential genes, such as housekeeping genes. (B) In some tumors, oncogenic signaling results in primarily hyperphosphorylated 4E-BPs. Additionally, many tumors express high levels of eIF4E. Excess free eIF4E leads to increased translation rates, especially of genes involved in proliferation, survival, and metastasis. These increased translation rates help to drive tumor progression. (C) In tumors treated with eIF4E ASOs, eIF4E levels are significantly reduced. Despite 4E-BP hyperphosphorylation, reduced eIF4E levels inhibit translation rates, causing growth arrest or even apoptosis in tumors. It is likely that this strategy would have broad-reaching applications for tumors with eIF4E overexpression, oncogenic signaling (leading to 4E-BP hyperphosphorylation), or both. Since tumors frequently rely on increased translation for high proliferation rates and other malignant properties, reducing eIF4E levels should have a greater impact on them than it would on normal cells.