XPO1 inhibition modulates the Wnt/β-catenin signaling pathway to reduce colorectal cancer tumorigenesis.

Abstract

Colorectal Cancer (CRC) is the second leading cause of cancer-related death in the U.S. and high-risk individuals face a notably higher likelihood of developing CRC based on their genetic background. Hence, there is a compelling need for innovative chemopreventive treatments aimed at minimizing CRC 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 CRC, and Selective Inhibitors of Nuclear Export (SINE) 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 CRC. Our findings indicate Eltanexor treatment inhibits expression of the common chemoprevention target in CRC, cyclooxygenase-2 (COX-2). This occurs by Eltanexor-dependent reduction of Wnt/{beta}-catenin signaling. Furthermore, XPO1 inhibition leads to forkhead transcription factor O subfamily member 3a (FoxO3a) nuclear retention, which can modulate {beta}-catenin/TCF transcriptional activity. 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 3-fold, along with decreased tumor size. Drug sensitivity assays using organoids from Apcmin/+ mice tumors show increased sensitivity to Eltanexor compared to wild-type organoids. Collectively, these findings highlight XPO1 as a potent target for CRC chemoprevention. SIGNIFICANCEIn this study, we show the XPO1 inhibitor, Eltanexor, reduces COX-2 by modulating the Wnt/{beta}-catenin signaling pathway and acts as an effective chemopreventive agent in the Familial Adenomatous Polyposis (FAP) mouse model, Apcmin/+ mice.