Communications Biology (Apr 2024)
Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin
- Karuna Mittal,
- Garrett W. Cooper,
- Benjamin P. Lee,
- Yongdong Su,
- Katie T. Skinner,
- Jenny Shim,
- Hunter C. Jonus,
- Won Jun Kim,
- Mihir Doshi,
- Diego Almanza,
- Bryan D. Kynnap,
- Amanda L. Christie,
- Xiaoping Yang,
- Glenn S. Cowley,
- Brittaney A. Leeper,
- Christopher L. Morton,
- Bhakti Dwivedi,
- Taylor Lawrence,
- Manali Rupji,
- Paula Keskula,
- Stephanie Meyer,
- Catherine M. Clinton,
- Manoj Bhasin,
- Brian D. Crompton,
- Yuen-Yi Tseng,
- Jesse S. Boehm,
- Keith L. Ligon,
- David E. Root,
- Andrew J. Murphy,
- David M. Weinstock,
- Prafulla C. Gokhale,
- Jennifer M. Spangle,
- Miguel N. Rivera,
- Elizabeth A. Mullen,
- Kimberly Stegmaier,
- Kelly C. Goldsmith,
- William C. Hahn,
- Andrew L. Hong
Affiliations
- Karuna Mittal
- Department of Pediatrics, Emory University School of Medicine
- Garrett W. Cooper
- Department of Pediatrics, Emory University School of Medicine
- Benjamin P. Lee
- Department of Pediatrics, Emory University School of Medicine
- Yongdong Su
- Department of Pediatrics, Emory University School of Medicine
- Katie T. Skinner
- Department of Pediatrics, Emory University School of Medicine
- Jenny Shim
- Department of Pediatrics, Emory University School of Medicine
- Hunter C. Jonus
- Department of Pediatrics, Emory University School of Medicine
- Won Jun Kim
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Mihir Doshi
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Diego Almanza
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Bryan D. Kynnap
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Amanda L. Christie
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Xiaoping Yang
- Broad Institute of MIT and Harvard
- Glenn S. Cowley
- Broad Institute of MIT and Harvard
- Brittaney A. Leeper
- Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute
- Christopher L. Morton
- Department of Surgery, St. Jude Children’s Research Hospital
- Bhakti Dwivedi
- Winship Cancer Institute, Emory University
- Taylor Lawrence
- Department of Pediatrics, Emory University School of Medicine
- Manali Rupji
- Winship Cancer Institute, Emory University
- Paula Keskula
- Broad Institute of MIT and Harvard
- Stephanie Meyer
- Department of Pediatric Oncology, Dana-Farber Cancer Institute
- Catherine M. Clinton
- Department of Pediatric Oncology, Dana-Farber Cancer Institute
- Manoj Bhasin
- Department of Pediatrics, Emory University School of Medicine
- Brian D. Crompton
- Broad Institute of MIT and Harvard
- Yuen-Yi Tseng
- Broad Institute of MIT and Harvard
- Jesse S. Boehm
- Broad Institute of MIT and Harvard
- Keith L. Ligon
- Broad Institute of MIT and Harvard
- David E. Root
- Broad Institute of MIT and Harvard
- Andrew J. Murphy
- Department of Surgery, St. Jude Children’s Research Hospital
- David M. Weinstock
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Prafulla C. Gokhale
- Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute
- Jennifer M. Spangle
- Winship Cancer Institute, Emory University
- Miguel N. Rivera
- Broad Institute of MIT and Harvard
- Elizabeth A. Mullen
- Department of Pediatric Oncology, Dana-Farber Cancer Institute
- Kimberly Stegmaier
- Broad Institute of MIT and Harvard
- Kelly C. Goldsmith
- Department of Pediatrics, Emory University School of Medicine
- William C. Hahn
- Department of Medical Oncology, Dana-Farber Cancer Institute
- Andrew L. Hong
- Department of Pediatrics, Emory University School of Medicine
- DOI
- https://doi.org/10.1038/s42003-024-06140-6
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 1 – 13
Abstract
Abstract Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.
