Researchers uncover key gene mutation driving chemotherapy resistance in colorectal cancer
MINNEAPOLIS/ST. PAUL (06/20/2025) — New research from a collaborative team from the University of Minnesota and University of Miami is providing important insights into a gene called XPO1 and its role in colorectal cancer. The findings were recently published in Cancer Research.
Researchers at the University of Miami discovered that a gene called XPO1 is often mutated in patients with endometrial and colorectal cancers. At the University of Minnesota, researchers focused on discovering why colorectal cancer cells with the XPO1 mutation are especially resistant to a common chemotherapy drug called Topoisomerase I inhibitors — known as Top1i — which is often used to treat colorectal cancer.
“Our preclinical findings reveal a new strategy to treat colorectal cancer, the third leading cause of cancer-related deaths in the US, with potential to extend to endometrial cancer,” said Hai Dang Nguyen, PhD, an assistant professor with the University of Minnesota Medical School and Masonic Cancer Center researcher. “By identifying specific DNA damage response pathways in XPO1-mutated tumors, our work opens a new avenue for precision therapies in these challenging cancers.”
The research team found that colorectal cancer cells with the XPO1 mutation activate stronger DNA repair responses after Top1i treatment, which may help them survive chemotherapy. However, when these cells were treated with Selinexor — a drug that blocks XPO1 protein— this effect was reversed. The study suggests that combining Top1i drugs with Selinexor may offer an effective treatment for patients with XPO1-mutant colorectal cancer.
“Our work identifies potential rationale to repurpose Selinexor to improve the efficacy of chemotherapeutic agents in XPO1-mutated tumors,” said Wannasiri Chiraphapphaiboon, PhD, a postdoctoral fellow in the Nguyen lab.
Researchers also observed that certain DNA repair proteins were mislocated within the cell due to the XPO1 mutation. They plan to study how this misplacement influences the cancer cells’ response to chemotherapy.
Further research will also explore whether the findings in colorectal cancer also apply to endometrial cancer patients with the same XPO1 mutation.
This research was supported by grants from the Masonic Cancer Center, Edward P. Evans Foundation, American Society of Hematology, the National Institutes of Health's National Heart, Lung, and Blood Institute [R01HL163011], and a career development award from the American Association for Cancer Research, which is supported by Merck.
###
About the University of Minnesota Medical School
The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians. Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. We acknowledge that the U of M Medical School is located on traditional, ancestral and contemporary lands of the Dakota and the Ojibwe, and scores of other Indigenous people, and we affirm our commitment to tribal communities and their sovereignty as we seek to improve and strengthen our relations with tribal nations. Learn more at med.umn.edu.
About the Masonic Cancer Center, University of Minnesota
The Masonic Cancer Center is the Twin Cities’ only Comprehensive Cancer Center, designated ‘Outstanding’ by the National Cancer Institute. As Minnesota’s Cancer Center, we have served the entire state for more than 30 years. Our researchers, educators, and care providers work to discover the causes, prevention, detection, and treatment of cancer and cancer-related diseases as well as provide whole-of-life care and resources for cancer survivors. Learn more at cancer.umn.edu.