eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Most breast cancers rely on estrogen receptor alpha (ER) activity, making them sensitive to ER inhibition.
• Resistance to endocrine therapy can develop due to ESR1 mutations or downstream pathway reactivation.
• Current ER antagonists have limited long-term efficacy as monotherapies.

Purpose of the Study:

• To investigate the role of translation initiation factor eIF4A in ER+ breast cancer.
• To evaluate the efficacy of eIF4A inhibition, alone and in combination, for overcoming endocrine resistance.
• To assess the clinical activity of eIF4A inhibitor zotatifin in patients with acquired resistance.

Main Methods:

• Assessed ER translation dependence on eIF4A.
• Utilized eIF4A inhibitors to reduce ER and cyclin D1 expression in preclinical models.
• Tested combination therapy with fulvestrant (ER degrader) and abemaciclib (CDK4 inhibitor).
• Conducted a Phase I clinical trial (NCT04092673) combining zotatifin with fulvestrant or fulvestrant/abemaciclib.

Main Results:

• eIF4A inhibition suppressed ER expression and proliferation in ligand-independent and ER-mutant models.
• Combination of eIF4A inhibitor and fulvestrant enhanced tumor growth inhibition in vitro and in vivo.
• Clinical trial showed responses, including durable regressions, in patients with acquired resistance to standard therapies.
• Treatment with zotatifin demonstrated an acceptable safety profile.

Conclusions:

• eIF4A is a viable therapeutic target for ER+ breast cancer, including resistant subtypes.
• Targeting eIF4A translation initiation offers a novel strategy to overcome endocrine resistance.
• Combination therapies involving eIF4A inhibition show potential for treating refractory ER+ breast cancer.