Abstract
Fusion-positive rhabdomyosarcoma (FP-RMS) arises from at least seven distinct oncofusions sharing a common PAX3/7 N-terminal DNA-binding domain fused to divergent C-terminal partners. How different oncofusions produce the same cancer was unknown. Here we show they are functionally interchangeable, associate with a shared protein network we term the common interactome, bind overlapping target genes, and drive a similar core transcriptional program. The common interactome contains the C-terminal partners of known oncofusions and a newly identified translocation, suggesting oncofusions arise by PAX3/7 DNA-binding domain fusing to interactome members. As loss of common interactome proteins impaired oncogenic activity we screened the interactome for shared vulnerabilities. This identified thymidylate synthase as preferentially required for FP-RMS growth. Accordingly, the antifolate pralatrexate suppressed growth across all seven oncofusions, in multiple human FP-RMS cell lines, and a patient-derived xenograft. These findings demonstrate that divergent FP-RMS oncofusions are functionally fungible through a shared interactome that defines common vulnerabilities.
Acknowledgements
We thank members of the FusOnc2 Consortium for feedback and support, services provided by the Duke Cancer Institute Proteomics & Metabolomics, and Sequencing & Genomic Technologies, and Functional Genomics core facilities. We would also like to thank Laura S. Hiemcke-Jiwa, PhD, for her expert support on tumor histology, Elizabeth A. Stewart, MD, David Hsu, MD, PhD, and Asa Karlstrom, PhD, for their expert support in PDX modeling, and Ninad Inamdar for PDX model validation.
Funding
This project was funded by the NCI (U54CA231630 to C.M.L. & C.M.C., F32CA236183 to S.P.Z., R01CA269272 to C.M.C., R01CA271603 to G.G.W., and UM1CA294108 to C.M.L.), shared resources supported by the NCI (P30CA014236) as well as the Foundation Children Cancer-free (Stichting Kinderen Kankervrij core funding) in the Netherlands, the St. Baldrick’s Foundation (to C.M.L.), and The Glenn and Stacy Schiffman Pediatric Cancer Research Fund (to C.M.L.).
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C.M.C. is co-Founder of Merlon Inc, a member of the External Advisory Board for the University of Colorado Cancer Center, has a cross appointment with Duke-NUS, is an ex-officio of the executive team for the Cancer Biology Training Consortium, has previously consulted for the Guidepoint Network in an ad hoc fashion, and received licensing reimbursement from Humacyte Inc. C.M.L. has received research funding from Ryvu, C.M.L.’s spouse is founder of Grid Therapeutics, and C.M.L.’s family has stock in LabCorp, and ThermoFisher. K.C.W. is a founder and equity holder at Tavros Therapeutics, Aurova Therapeutics, and Celldom, a scientific advisor and equity holder at Stelexis Therapeutics and Decrypt Bio, and has performed consulting work for Retroviral Proviromics, Guidepoint Global, Bantam Pharmaceuticals, Quantum SI, and Apple Tree Partners. R.A.S. is principal investigator on two investigator-initiated studies, for which research funding is contributed to the institution for the conduct of the study (Takeda, Pfizer). None of these relationships provided salary or research support, nor did they play a role in the study design, data collection, data analysis, or decision to publish for this project. The remaining authors have no conflicts to disclose.
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Zimmerman, S.P., Delaney, C.D., Lau, B.K. et al. Fusion-positive rhabdomyosarcoma oncofusions share a common interactome. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73749-y
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DOI: https://doi.org/10.1038/s41467-026-73749-y
