Gene Discovery Opens New Path for Colorectal Cancer Treatment

Researchers from the University of Miami Leonard M. Miller School of Medicine have identified a genetic mutation that could lead to innovative therapies for colorectal cancer. Dr. Justin Taylor and his team conducted a preclinical study published in Cancer Research, focusing on a mutation in the gene encoding Exportin-1 (XPO1), a cellular regulator involved in transporting proteins and RNA between the nucleus and cytoplasm. The mutation, known as XPO1 R749Q, co-occurs with other mutations that cause DNA damage and contributes to chemoresistance.

The study revealed that this specific mutation makes tumor cells resistant to irinotecan, a common chemotherapy for colorectal cancer, by enhancing DNA repair mechanisms that counteract the drug-induced damage. Interestingly, when the researchers applied selinexor, an XPO1 inhibitor already approved for multiple myeloma, combined with irinotecan, they observed significant tumor shrinkage in preclinical models. This suggests a promising combination therapy that could overcome resistance in colorectal and possibly endometrial cancers, which can also harbor this mutation.

Initial investigations also traced the mutation’s origins to earlier research on blood cancers, where XPO1 mutations were linked to leukemia and lymphoma. In analyzing data from over 217,000 cancer patients, the team found the mutation in 96 solid tumors, primarily colorectal and endometrial cancers, although it remains a rare mutation.

Further experiments demonstrated that the XPO1 R749Q mutation does not accelerate tumor growth but provides resistance to DNA-damaging agents by increasing DNA repair activity, mediated by proteins like replication protein A (RPA). Importantly, targeting XPO1 with selinexor effectively killed tumor cells, providing a new strategy to counteract chemoresistance and improve treatment outcomes.

Collaborative efforts with the University of Minnesota have deepened understanding of how the mutation influences DNA repair pathways, offering additional avenues for therapeutic intervention. The ongoing research aims to evaluate the combination of XPO1 inhibition with immunotherapies and to explore the mutation’s role in endometrial cancer, which impacts thousands of women annually.

This groundbreaking research highlights the potential of targeted genetics in designing more effective, personalized treatments for colorectal cancer and other solid tumors, ultimately aiming to translate these findings into clinical practice.