ArticleCancer research communications2025
The XPO1 Inhibitor Eltanexor Modulates the Wnt/β-Catenin Signaling Pathway to Reduce Colorectal Cancer Tumorigenesis.
Article in Cancer research communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Colorectal cancer is the second leading cause of cancer-related death in the United States and high-risk individuals face a notably higher likelihood of developing colorectal cancer based on their genetic background. Hence, there is a compelling need for innovative chemopreventive treatments aimed at minimizing colorectal cancer tumorigenesis. Exportin 1 (XPO1; also referred to as CRM1) plays a pivotal role in transporting proteins from the nucleus to the cytoplasm. Various cancers overexpress XPO1, including colorectal cancer, and selective inhibitors of nuclear export compounds, such as eltanexor (KPT-8602), have been developed to target XPO1. Eltanexor demonstrates fewer adverse effects than its precursors and is currently under evaluation in phase I/II clinical trials. This research evaluates eltanexor as a chemopreventive agent for colorectal cancer. Our findings indicate that eltanexor treatment inhibits expression of the common chemoprevention target in colorectal cancer, COX-2. This occurs by eltanexor-dependent reduction of Wnt/β-catenin signaling. Furthermore, XPO1 inhibition leads to forkhead transcription factor O subfamily member 3a nuclear retention, which can modulate β-catenin/TCF transcriptional activity. The in vivo oral treatment of eltanexor to Apcmin/+ mice (a mouse model for familial adenomatosis polyposis) was well tolerated and reduced tumor burden by approximately threefold, along with decreased tumor size. Drug sensitivity assays using organoids from Apcmin/+ mice tumors showed increased sensitivity to eltanexor compared with wild-type organoids. Collectively, these findings highlight XPO1 as a potent target for colorectal cancer chemoprevention. SIGNIFICANCE: In this study, we show the XPO1 inhibitor eltanexor acts as an effective colorectal cancer chemopreventive agent both in vivo and in vitro. This occurs by reducing COX-2 expression by modulating the Wnt/β-catenin signaling pathway. Collectively, these findings highlight XPO1 as a potent target for colorectal cancer chemoprevention.
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