Efficacy of an XPO1 inhibitor in combination with irinotecan in a preclinical colorectal cancer model.

Background: Irinotecan is a topoisomerase I inhibitor that is commonly used as a chemotherapeutic regimen for the treatment of metastatic colorectal cancer (CRC) by producing cytotoxic DNA damage. However, drug resistance frequently occurs, underscoring the importance of developing newer treatment strategies. The nuclear export protein XPO1 is an important mediator in the transport of proteins involved in cell cycle regulation and XPO1 inhibitors have shown activity as a single agent and in combination with DNA damaging agents. Methods: Using preclinical CRC PDX and cell line models, we evaluated the therapeutic potential of selinexor or eltanexor (XPO1 inhibitors), as a single agent and in combination with chemotherapeutic agents. Results: We show a combination effect with eltanexor + irinotecan in one of our CRC PDX models and observed synergistic sequential treatment effects in three of our CRC cell lines. In our mechanistic studies, elevation of p53 nuclear/cytoplasmic ratio and the activation of H2A.X suggests that the addition of eltanexor to irinotecan may facilitate its cellular effects by preventing the repair of DNA damage and inducing apoptosis. Conclusion: This preclinical CRC study demonstrates that combining eltanexor with irinotecan enhances cytotoxicity and anti-tumor effects in a subset of preclinical CRC PDX and cell line models, and that sequential treatment with irinotecan first may be most effective in inducing these treatment effects in the combination responsive CRC models.