TABLE 1.
Targeting eIF4F-dependent mRNA translation for cancer treatment
| Cancer type | Dysregulated translation factors/ pathways | Drugs/genetic manipulation | Effect of drug/genetic manipulation | Target mRNAs/proteins | Reference |
|---|---|---|---|---|---|
| Pancreatic cancer | MNK1/2–p-eIF4E axis | eIF4ES209A knock-in mice or eFT508 | Disrupts metabolic adaptation and reduces tumor growth | Genome-wide translatome analysis identified 445 mRNAs translationally downregulated in the fasted liver of eIF4ES209A mice that are upregulated in wild types, including Hmgcs2, Ppara | Yang et al. 2024 |
| Upregulation of eIFG1 drives tumor progression and immune evasion | SBI-756 | SBI-756, by the inhibition of eIF4E-eIF4G1 interaction, disrupts desmoplastic and immunosuppressive TME and increases antitumor immunity (increased infiltration of CD8+ T cells) | SBI-756 inhibits integrinβ1 translation and suppresses tumor growth by targeting FAK-ERK/Akt signaling pathway | He et al. 2024 | |
| Soft tissue sarcomas (STC) | MNK1/2–p-eIF4E axis | ETC-168 | ETC-168 reduces cell proliferation in vitro and reduces tumor growth in vivo. ETC-168, in combination with MCL1 inhibitor S63845, shows synergistic antiproliferative effects in vitro. |
ETC-168 inhibits MNK1/2, and downregulates E2F1, FOXM1, WEE1 | Ke et al. 2021 |
| Breast cancer | MNK1/2–p-eIF4E axis | MNK1 knockout | Reduces stem cell-like properties (less tumorsphere formation) | Multiomics of MNK1-null cells showed a reduction in glycolysis and increased reliance on OxPhos | Preston et al. 2024 |
| eIF4ES209A knock-in mice or Merestinib | Reduces lung metastasis formation by inhibiting neutrophil accumulation | Translationally downregulates BCL-2 and MCL-1 | Robichaud et al. 2018 | ||
| Increased eIF4F-dependent translation | MG-002 | Inhibits cap-dependent mRNA translation initiation by targeting eIF4A and reduces breast tumor growth and metastasis. It also shows synergistic anticancer effects in combination with doxorubicin. |
Inhibits translation of c-Myc, Cyclin D1 | Cencic et al. 2024 | |
| Prostate cancer | PTEN loss activated MNK1/2–p-eIF4E axis | eFT508 | Decreases MDSC infiltration and enhances CD8+ T cell activity | Inhibits translation of Hgf, Spp1, Bgn mRNAs | Brina et al. 2023 |
| eIFG1 is increased | 4EGI-1 | Reduces colony formation | Inhibits Cyclin D1, CDH2, SNAIL1 | Jaiswal et al. 2018 | |
| Melanoma | MNK1/2–p-eIF4E axis | SEL201 | Inhibits metastasis | Inhibition of MNK1/2 downregulates proteins involved in extracellular matrix remodeling and cell adhesion, including ANGPTL4 | Yang et al. 2020b |
| Multiple myeloma | Deregulated eIF4F-dependent translation | 4EGI-1 | Increases apoptosis of cancer cells | Inhibits eIF4G-eIF4E interaction and upregulates the expression of proapoptotic protein NOXA | Descamps et al. 2012 |
| NSCLC | Upregulated eIF4F-dependent translation | eFT226 | Enhances the efficacy of KRAS G12C inhibitors | Inhibits eIF4A and represses BCL-2 expression | Nardi et al. 2023 |
| 4EGI-1 | Inhibits cell proliferation and increases apoptosis of cancer cells | Inhibits the expression of c-Myc, BCL-2, cyclin D1, survivin | De et al. 2019 | ||
| Glioma | Upregulated eIF4F-dependent translation | 4EGI-1 | Increases apoptosis of cancer cells | Triggers ER stress. Inhibits c-Myc, cyclin D1 and D2, survivin translation. Upregulates ER stress related factors: p-PERK, CHOP. | Wu et al. 2016 |
| BAY1143269 | Inhibits angiogenesis and tumor growth | Inhibits MNK1 and suppresses VEGF, c-Myc, Cyclin D1 and A1, CDK2, ZEB1, SNAIL and SLUG expression | Wan et al. 2022 | ||
| B-cell lymphoma | eIF4G1 | SBI-756 | Shows a synergistic anticancer effect in combination with venetoclax | Inhibits eIF4G-eIF4E interaction. Genome-wide translatome analysis following SBI-756 treatment showed a reduction of anti-apoptotic and ribosomal proteins. | Herzog et al. 2021 |
| Papillary thyroid cancer (resistance to BET inhibitors) | Increased MNK1/2–p-eIF4E axis | CGP57380 or MNK1/2 siRNA | Reverses resistance to BET inhibitors | MNK inhibition in combination with BET shows improved anticancer effects. Targets affected by the combination are yet to be identified. | Pham et al. 2019 |
| Melanoma and breast cancer (resistance against CDK4/6 inhibitors) | Increased MNK1/2–p-eIF4E axis | SEL201 | MNK inhibition reverses CDK4/6 inhibitor palbociclib in melanoma and breast cancer | Downregulates cell-cycle progression and mitosis-related proteins, including AURKB, TPX2, and survivin | Prabhu et al. 2023 |
| Glioblastoma (radiosensitivity) | eIF4A | (-)-SDS-1–021 | Inhibits eIF4A and enhances the radiosensitivity of tumor cells by impairing DNA damage repair | Translatome analysis showed enrichment of mRNAs related to DNA repair pathway | Lehman et al. 2022 |
