Manasterski, P.J., Danks, M.R., Thomson, J.P. et al. (17 more authors) (2025) Genomics‐led approach to drug testing in models of undifferentiated pleomorphic sarcoma. Molecular Oncology. ISSN 1574-7891
Abstract
Undifferentiated pleomorphic sarcoma (UPS) is a rare cancer with limited systemic treatment options and poor outcomes. To seek novel therapeutic interventions, we undertook mutational analysis of 20 UPS patient tumours, four established UPS cell lines and three patient-derived xenograft (PDX) models. Frequently mutated genes were uncommon; in contrast, copy number (CN) events were common with CN gain frequently observed at genes including JUN, EGFR and CDK6 and loss at WNT8B, RB1 and PTEN. Analysis of overlapping genomic changes between patient tumours and PDX models or cell lines revealed druggable events. A selected panel of drugs targeting these was analysed in in vitro UPS models demonstrating that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib is synergistic in combination with the fibroblast growth factor receptor (FGFR) inhibitor infigratinib. This was further confirmed to be efficacious in an ex vivo tumour slice model. Taken together, our results demonstrate the rationale for utilising genomic data to identify drug classes targeting druggable events in low-prevalence cancers and indicate that trametinib alone or in combination with infigratinib should be further explored for clinical UPS management.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | drug screening; patient-derived xenograft; tumour slices; undifferentiated pleomorphic sarcoma; whole exome sequencing |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 03 Jun 2025 11:04 |
Last Modified: | 03 Jun 2025 11:04 |
Status: | Published online |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/1878-0261.70059 |
Sustainable Development Goals: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:227300 |