The XPO1 Inhibitor Eltanexor Modulates the Wnt/β-Catenin Signaling Pathway to Reduce Colorectal Cancer Tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Colorectal cancer (CRC) is a leading cause of cancer death, necessitating novel chemopreventive strategies.
• High-risk individuals have a greater genetic predisposition to CRC.
• Exportin 1 (XPO1) is overexpressed in various cancers, including CRC, making it a potential therapeutic target.

Purpose of the Study:

• To evaluate eltanexor, a selective XPO1 inhibitor, as a chemopreventive agent for colorectal cancer.
• To investigate the molecular mechanisms underlying eltanexor's chemopreventive effects.
• To assess the efficacy and tolerability of eltanexor in preclinical models of CRC.

Main Methods:

• In vitro studies using organoids and in vivo studies using Apcmin/+ mice.
• Assessment of eltanexor's impact on key signaling pathways, including Wnt/β-catenin.
• Evaluation of XPO1 inhibition's effect on transcription factors like FOXO3a.
• Measurement of tumor burden, size, and drug sensitivity.

Main Results:

• Eltanexor treatment significantly reduced tumor burden (approximately threefold) and tumor size in Apcmin/+ mice.
• Eltanexor inhibited cyclooxygenase-2 (COX-2) expression, a known CRC chemoprevention target.
• The drug's efficacy was linked to the modulation of the Wnt/β-catenin signaling pathway and nuclear retention of FOXO3a.
• Organoids derived from Apcmin/+ mouse tumors exhibited increased sensitivity to eltanexor compared to wild-type organoids.

Conclusions:

• XPO1 is a potent molecular target for colorectal cancer chemoprevention.
• Eltanexor demonstrates significant chemopreventive potential against colorectal cancer through inhibition of XPO1.
• The findings support further clinical investigation of eltanexor for CRC chemoprevention.