Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Enhanced protein synthesis supports cancer cell survival, proliferation, and chemotherapy resistance.
• Multiple myeloma (MM) exhibits high activity in translation regulatory pathways, suggesting sensitivity to therapies targeting protein synthesis.

Purpose of the Study:

• To identify novel therapeutic vulnerabilities in multiple myeloma (MM) by screening translation apparatus components.
• To investigate synthetic lethal interactions between translation factors and dexamethasone (DEX) in MM.

Main Methods:

• Conducted a focused RNA interference (RNAi) screen targeting components of the translation apparatus in MM.
• Utilized small molecules to inhibit the eukaryotic initiation factor 4F (eIF4F) complex and assessed its effects on MM cell lines and primary samples.

Main Results:

• Suppression of all three subunits of the eIF4F complex synergized with dexamethasone (DEX) to induce cell death in MM.
• Inhibition of eIF4F reduced cell survival and DEX resistance in MM cell lines and primary human samples.
• eIF4F inhibition decreased levels of MYC and myeloid cell leukemia 1, key survival factors in MM, which also synergized with DEX upon independent suppression.

Conclusions:

• Targeting the eIF4F cap-binding complex presents a novel therapeutic strategy for multiple myeloma.
• Inhibition of eIF4F in MM demonstrates pleiotropic effects, offering a unique therapeutic opportunity by impacting key survival pathways.