Poster Session - Abstract # 7

Inhibition of Xpo1 in Colorectal Cancer

Andrew E. Evans, Dan A. Dixon

Department of Molecular Biosciences, The University of Kansas, Lawrence, KS, USA

Colorectal Cancer (CRC) is the second leading cause of cancer death in the U.S. affecting both men and women.  Exportin 1 (Xpo1; also known as CRM1) transports proteins with a leucine-rich nuclear export signal from the nucleus to the cytoplasm.  Xpo1 is known to be overexpressed in multiple cancers, including CRC, and interacts with over 1000 different proteins.  The overexpression of Xpo1 can lead to the excessive removal of tumor suppressors and inflammatory regulating proteins from the nucleus.  Removal of these proteins renders them inactive and promotes the tumorigenesis of CRC.  Selective Inhibitors of Nuclear Export (SINE) compounds are a new class of drugs that inhibit Xpo1.  Selinexor is considered the first-generation of SINE compounds and has FDA approval to treat patients with Large B-Cell Lymphoma and Myeloma.  Eltanexor is a second-generation compound that is currently in clinical trials for multiple cancer types.  The benefit of Eltanexor is that it exhibits fewer side effects than Selinexor, due to its inability to penetrate the blood-brain barrier.  The treatment effects of SINE compounds on CRC remains largely unknown.  Here we propose that Xpo1 poses as a strong target for the treatment of CRC.  Our results have shown that by western blot and immunofluorescence analysis, there is a decrease in the Xpo1 protein levels in HCT116 cells when they are treated with a SINE compound.  Interestingly, we have shown through western blot analysis, a decrease in the protein Human Antigen R (HuR) when cells are treated with a SINE compound. HuR is a mRNA binding protein overexpressed in CRC that binds and transports oncogenic mRNAs from the nucleus to the cytoplasm.  Next, we analyzed Eltanexor’s tumor prevention ability in the CRC mouse model, APC^min/+ mice.  From this pilot study, we observed a significant (p<0.01), ~70% reduction, in intestinal tumor number.  Along with showing a reduction in tumor burden, the treated mice showed a significant (p<0.001) decrease in the frequency of tumors greater than 1mm.  Together, these results highlight the potential for using Xpo1 inhibitors as a chemopreventative method to prevent the development of CRC and suggest that HuR reduction assists in SINE compounds' capability to inhibit CRC cells.  Future experiments will aim to further characterize the interaction between HuR and Xpo1.  We will also further examine the mechanisms that allow SINE compounds to inhibit intestinal tumor burden and size in APC^min/+ mice.