Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) is lethal due to therapy resistance.
• Resistance is often driven by androgen receptor (AR) splice variants and altered protein synthesis.
• Novel therapeutic strategies are needed to overcome resistance mechanisms in mCRPC.

Purpose of the Study:

• To identify novel therapeutic strategies to overcome resistance in mCRPC.
• To investigate the potential of targeting Exportin-1 (XPO1) and EIF4A1 in combination.

Main Methods:

• High-throughput screening of 2,480 mechanistically annotated compounds in advanced prostate cancer models.
• Matrix-based combination screening to identify synergistic drug interactions.
• Evaluation of dual XPO1 and EIF4A1 inhibition in patient-derived organoids and in vivo xenografts.

Main Results:

• Exportin-1 (XPO1)-mediated nuclear export is a critical dependency in mCRPC.
• Synergistic combination of XPO1 and EIF4A1 inhibitors disrupted oncogenic protein networks, including AR/AR-V7.
• Dual inhibition induced apoptosis and suppressed cell-cycle and metabolic programs.
• Significant anti-tumor effects were observed in diverse models at low drug doses.

Conclusions:

• Co-inhibition of nuclear export and translation initiation is a therapeutic vulnerability in mCRPC.
• Dual targeting of XPO1 and EIF4A1 overcomes AR-driven resistance mechanisms.
• This combination therapy demonstrates potent anti-tumor responses and is suitable for clinical translation.