학술논문
Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin
Document Type
article
Author
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
Source
Communications Biology, Vol 7, Iss 1, Pp 1-13 (2024)
Subject
Language
English
ISSN
2399-3642
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.