Abstract 2358: XPO1 inhibition serves as an effective chemoprevention strategy in colorectal cancer mouse models

Abstract Background: Familial Adenomatous Polyposis (FAP) is a hereditary condition resulting in a 100% chance of developing colorectal cancer (CRC) if left untreated. Individuals with FAP often undergo colectomies in their 20s. Thus, there is a critical need for novel chemopreventive approaches to reduce CRC risk in FAP patients. XPO1 is a nuclear export protein overexpressed in multiple cancer types, including CRC. The overexpression of XPO1 has been shown to promote tumorigenesis by excessively removing numerous tumor suppressors from the nucleus. To combat XPO1 overexpression, Selective inhibitors of Nuclear Export (SINE) compounds have been developed. One of those compounds, Eltanexor (KPT-8602), is a second-generation SINE compound currently in Phase I/II clinical trials. Eltanexor has been shown to exhibit fewer side effects compared to its predecessors. Methods and Results: Our research shows that XPO1 is overexpressed in multiple different stages of CRC and in Apcmin/+ mice, a FAP mouse model, adenomas. In xenograft studies with HCT116 cells, Eltanexor significantly inhibits CRC tumorigenesis. Further analysis revealed that Eltanexor reduced cyclooxygenase-2 (COX-2) expression, a key target in chemoprevention, by downregulating Wnt/β-catenin signaling. Deletion mapping and TOPFlash luciferase assays confirmed Eltanexor’s modulation of Wnt/β-catenin activity. Notably, Eltanexor enhanced nuclear retention of Forkhead Box O3a (FOXO3a), a known XPO1 cargo and Wnt/β-catenin regulator. Moreover, organoid drug sensitivity assays we performed indicated that Apcmin/+ adenoma organoids are more sensitive to XPO1 inhibition compared to wild-type intestinal organoids. To explore Eltanexor as a chemopreventive compound, we treated Apcmin/+ mice with Eltanexor for 6 weeks, leading to a significant 62% decrease in tumor burden and a reduction in tumor size. Moreover, to further evaluate Eltanexor’s potential role in chemoprevention, Eltanexor was administered to Apcmin/+ mice with celecoxib, a COX-2 inhibitor shown previously to effectively limit Apcmin/+ mice tumorigenesis. Our results revealed mice administered the combined treatment experienced a significant >80% reduction in tumor burden and diminished tumor size. Importantly, both Eltanexor as a monotherapy and the combination treatment were well-tolerated, with no observed toxicity in the treated mice. Conclusions: Our findings show XPO1 inhibition using the small molecule Eltanexor results in inhibition of the Wnt/ β-catenin signaling pathway, a crucial pathway in CRC tumorigenesis. Furthermore, we show that Eltanexor treatment is an effective chemoprevention strategy in Apcmin/+ mice, a FAP mouse model. These findings highlight a promising chemopreventive strategy for high-risk CRC individuals. Citation Format: Andrew E. Evans, Alexa N. Magstadt, Dan A. Dixon. XPO1 inhibition serves as an effective chemoprevention strategy in colorectal cancer mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2358.