Define the molecular effects of wildtype and mutant XPO1 on gene expression, splicing, and translation.
Given the known role of XPO1 in the export of small nuclear RNA (snRNA) and ribosomal RNA (rRNA) via the binding of RNA binding proteins, we hypothesize that cancer-associated alterations in XPO1 may impact RNA splicing and/or mRNA translation. We have generated several genetically engineered models to allow endogenous expression of the XPO1 E571K hotspot mutation, including conditional knockin mice. I have demonstrated through a variety of proteomic, biochemical, structural, and molecular studies that XPO1E571K affects recognition of its cargo’s NES and results specifically in altered export of NFκB and NFAT transcription factor proteins. The aim of my first project is to continue to study the extent of how the XPO1 E571K alters nuclear export and to explore whether RNA export and consequent mRNA splicing and translation, are affected through the mislocalization of RNA binding proteins.
Determine how XPO1 mutations sensitize cells to XPO1 inhibition and whether XPO1E571K creates dependencies that might be exploited for therapeutic purposes.
Precision oncology is the principle that not all tumors will respond the same to therapies and that genetic or other biomarkers might predict those most likely to respond. One goal of our research is to develop new targeted therapies with activity in XPO1 overexpressing or mutant cancers. Based on our preliminary data, we have demonstrated that mutant XPO1 increases sensitivity to small molecules binding XPO1. We now want to study the effects of nuclear export inhibition in XPO1 overexpressing cells to determine the mechanism behind this increased sensitivity to help discover clues as to how better to target XPO1E571K, as well as wild-type XPO1. Furthermore, we are now performing a reverse genetic screen to investigate therapeutic vulnerabilities in XPO1 WT or E571K cells through synthetic lethal interactions. We will work to translate these findings into targets for early phase clinical trials. We hypothesize XPO1 E571K allows small molecule inhibitors of XPO1 to bind more tightly to the NES binding pocket to create stronger inhibition of nuclear export and increased cell death.
