Poster abstracts
Poster number 31 submitted by Wannasiri Chiraphapphaiboon
XPO1 and topoisomerase-1 inhibitors synergistically sensitize XPO1-mutant colorectal cancers
Wannasiri Chiraphapphaiboon (Masonic Cancer Center, Department of Pharmacology, University of Minnesota), Tulasigeri M. Totiger (Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine), Justin Taylor (Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine), Hai Dang Nguyen (Masonic Cancer Center, Department of Pharmacology, University of Minnesota)
Abstract:
Exportin 1 (XPO1) is a major export transporter that is responsible for nuclear-cytoplasmic transport of proteins and RNAs. XPO1 is commonly overexpressed in different cancers, highlighting an attractive therapeutic target. In our current study, pan-cancer analysis revealed that XPO1 is mutated (p.R749Q) in colorectal cancers. We used CRISPR-Cas9 to generate XPO1-R749Q mutation at the endogenous locus in HCT116 and LS174T colorectal cell lines. Intriguingly, XPO1-R749Q mutant cells are more resistant to standard chemotherapeutic and DNA-damaging agents. Mechanistically, we found that XPO1-R749Q mutant cells displayed lower DNA damage levels compared to wild-type cells following camptothecin (CPT) exposure. Interestingly, albeit lower DNA damage levels, CPT-treated XPO1-R749Q mutants induced higher RPA phosphorylation in γH2AX-positive cells. These results suggest that XPO1-R749Q cells hyper-activate RPA phosphorylation to prevent DNA damage. In line with this notion, we found that selinexor, an inhibitor that targets XPO1, reduced CPT-induced RPA phosphorylation. Moreover, selinexor treatment combined with the standard of care agent, irinotecan synergistically sensitized XPO1-R749Q mutant cells. Taken together, our results suggest that increased RPA phosphorylation could mediate resistance to DNA-damaging therapies in XPO1-R749Q mutant cells. We further demonstrate that impairing RPA phosphorylation by selinexor may provide a preclinical rationale to treat colorectal cancer patients with XPO1 mutations to overcome resistance to chemotherapeutic agents.
Keywords: Exportin 1, Chemotherapeutic resistance, Colorectal cancers