XPO1 R749Q

"XPO1 inhibition with selinexor synergized with chemotherapy in XPO1 R749Q mt cells in vitro and overcame resistance to irinotecan in vivo in xenograft mice models. This study sheds novel insights into the role of nuclear export in cancers. This study sheds novel insights into the role of nuclear export in cancers. Specifically, XPO1 R749Q mutations are enriched in TMB-H endometrial and colon cancers and increase nuclear export of key proteins that confer resistance to therapies using DNA-damaging agents. Our current work aims to identify novel therapies that can overcome resistance to DNA-damaging therapies seen in XPO1 mutant cells, such as immune checkpoint inhibitor (ICI) therapy given the co-occurrence with POLE mutations and recent reports of high level of response to ICI therapy in TMB-H and POLE mt colorectal cancers."

The combination of selinexor and irinotecan showed high levels of synergy in vitro. Our study established the biological and mechanistic consequences of XPO1 R749Q mutations in cancer, thereby having a significant positive impact on the treatments of patients with cancer. Further work is ongoing for the identification of cargo proteins transported by mutated XPO1 that connect the effects of XPO1 R749Q mutation on nuclear export to response to DNA damage, mTOR signaling and XPO1 inhibition in tumors in vitro and in vivo.