In a groundbreaking preclinical study unveiled this June, Dr. Justin Taylor, a distinguished physician-scientist at the Sylvester Comprehensive Cancer Center affiliated with the University of Miami Miller School of Medicine, has revealed pioneering insights into a novel approach for combating colorectal cancer. Recognized for his work by the prestigious Stanley J. Glaser Foundation Research Award, Dr. Taylor’s research holds promise for redefining treatment strategies for one of the most prevalent cancers in the United States. This study, published online first in the eminent journal Cancer Research, delves deep into the molecular underpinnings of colorectal cancer resistance and offers innovative therapeutic avenues.
Central to this investigation is the mutation of the gene encoding Exportin-1 (XPO1), a crucial cellular regulator responsible for the nucleocytoplasmic transport of proteins and RNA. The specific mutation under scrutiny, XPO1^R749Q, has been identified as a rare but significant factor in colorectal as well as endometrial cancers. While the mutation itself does not accelerate tumor proliferation, it plays a key role in enabling tumor cells to resist chemotherapeutic agents, particularly irinotecan, a DNA replication inhibitor commonly used in colorectal cancer treatment protocols.
Dr. Taylor’s team utilized CRISPR-Cas9 genome editing to introduce the XPO1^R749Q mutation into human colorectal tumor cell lines to precisely interrogate its functional consequences. Their experiments elucidated that this mutation confers resistance to irinotecan by enhancing cellular DNA repair mechanisms. Specifically, the mutation appears to augment the activity of Replication Protein A (RPA), a pivotal protein involved in the DNA damage response, thereby enabling tumor cells to survive despite the genotoxic stress induced by chemotherapy.
Further compounding the complexity of these tumors, XPO1^R749Q mutations were found to often co-occur with mutations in the POLE gene—another mutation associated with a hypermutated state and extensive DNA damage. This co-mutation pattern underscores a sophisticated balance within tumor cells, wherein the DNA damage inflicted by POLE mutations is counteracted by the heightened repair capability driven by XPO1^R749Q, facilitating chemoresistance.
Encouragingly, the study revealed that targeting XPO1 with the selective inhibitor selinexor can effectively kill tumor cells harboring the R749Q mutation. Selinexor is already clinically approved for certain hematologic malignancies and is showing potential in endometrial cancer maintenance therapy. When combined with irinotecan, selinexor produced significantly reduced tumor volumes in preclinical colorectal cancer models, suggesting a synergistic therapeutic effect capable of overcoming existing drug resistance.
One of the most compelling findings is that the combination of selinexor and irinotecan may prove effective even in colorectal tumors without the XPO1 mutation. This is due to the fact that elevated levels of wild-type XPO1 are frequently observed across various solid tumors, which may render them susceptible to XPO1 inhibition. Hence, Dr. Taylor posits that this dual-drug regimen could have far-reaching applications beyond mutation-specific contexts.
Dr. Jaime Merchán, co-leader of the Translational and Clinical Oncology Research Program at Sylvester, emphasizes the clinical viability of these findings. He points out that this work not only provides a scientific rationale for new treatment protocols but also creates a viable path for transitioning from bench research to bedside application, potentially reshaping standard care for patients afflicted with advanced colorectal cancer.
The research owes much to extensive data analysis encompassing genomic profiles from over 217,000 cancer patients, enabling the identification of XPO1^R749Q mutation prevalence across solid tumors. This massive dataset highlights the mutation’s rarity but also its critical importance in the broader context of chemoresistance. These insights are the product of collaborative efforts between Sylvester and the Masonic Cancer Center at the University of Minnesota, where molecular oncologist Hai Dang Nguyen provided key contributions to unraveling the mutation’s mechanistic effects.
Future research spearheaded by Dr. Taylor and his postdoctoral associate Tulasigeri M. Totiger is set to explore whether the mechanistic pathways influenced by XPO1^R749Q operate similarly in endometrial cancer models. In addition, there is a strategic plan to assay the efficacy of combining selinexor with immunotherapy agents to amplify anti-tumor immune responses, thus expanding the therapeutic repertoire against resistant solid tumors.
This innovative study is supported by funding from the U.S. National Institutes of Health and institutional resources from Sylvester Comprehensive Cancer Center. Dr. Taylor underscores the importance of translational science in his approach, aiming to rapidly deliver tangible benefits for patients by leveraging molecular insights garnered from leukemia research and applying them to distinctly different solid tumor types.
As the research community grapples with the challenge of overcoming chemotherapy resistance—a major barrier to effective cancer treatment—this study shines a beacon of hope. It pioneers a new conceptual framework by integrating molecular genetics, DNA repair biology, and pharmacology to surmount obstacles that have long plagued colorectal cancer therapy. The implications of these findings could revolutionize clinical workflows and improve survival outcomes for countless patients.
By illuminating the interplay between nuclear export mechanisms and DNA damage repair pathways, Dr. Taylor’s work not only deepens our understanding of tumor cell biology but also paves the way for the development of next-generation therapeutics that exploit vulnerabilities in the cancer cell’s defense systems. If successfully translated into the clinic, this could mark a paradigm shift in how clinicians approach treatment-resistant colorectal and endometrial cancers.
The Stanley J. Glaser Foundation Research Award that enabled this research serves to recognize and propel outstanding faculty scientists by providing critical financial support for high-impact projects. With this backing, Dr. Taylor’s groundbreaking investigation is poised to move beyond preclinical stages toward clinical trials, with the ultimate goal of delivering more effective, personalized cancer therapies.
As cancer remains among the leading causes of morbidity and mortality worldwide, discoveries such as these underscore the indispensable role of genetic and translational research in combating this complex disease. Through strategic targeting of molecular pathways like those involving XPO1 mutations, the future of oncology promises more tailored, efficacious treatments that can better overcome drug resistance and improve long-term patient prognosis.
Subject of Research: Targeting XPO1 R749Q Mutations to Overcome Chemoresistance in Colorectal and Endometrial Cancers
Article Title: XPO1R749Q Mutations Co-occur with POLE Mutations in Cancer and can be Targeted to Overcome Chemoresistance
News Publication Date: June 18, 2025
Web References:
- University of Miami/Taylor Lab
- Sylvester Comprehensive Cancer Center
- Cancer Research Journal – Article DOI
References:
- Taylor J, Nguyen HD, et al. XPO1R749Q Mutations Co-occur with POLE Mutations in Cancer and Can be Targeted to Overcome Chemoresistance. Cancer Research. 2025.
Image Credits: Photo by Sylvester Comprehensive Cancer Center
Keywords: Colorectal cancer, colon cancer, molecular genetics, mutation, cancer, chemoresistance, XPO1, selinexor, irinotecan, DNA repair, CRISPR-Cas9, translational oncology
