Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma

Manasterski, Piotr; Danks, Molly R.; Thomson, John P.; Muir, Morwenna; Lee, Martin; Dawson, John C.; Amaral, Ana Teresa; Diaz-Martin, Juan; Moura, David S.; Martín-Broto, Javier; Alsaadi, Ali; Salter, Donald M.; Oswald, Ailsa J.; Grimes, Graeme R.; Hayward, Larry; Hupp, Ted; Sisley, Karen; Huang, Paul H.; Carragher, Neil O.; Brunton, Valerie G.

Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma

[Data accessibility] The genomic data generated for patient tumours, cell lines and PDX models presented in this manuscript are currently under upload to the European Genome-Phenome Archive (EGA: https://ega-archive.org/) and will be available upon reasonable request. The WGS reads from UPS samples...

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Detalles Bibliográficos
Autores:	Manasterski, Piotr, Danks, Molly R., Thomson, John P., Muir, Morwenna, Lee, Martin, Dawson, John C., Amaral, Ana Teresa, Diaz-Martin, Juan, Moura, David S., Martín-Broto, Javier, Alsaadi, Ali, Salter, Donald M., Oswald, Ailsa J., Grimes, Graeme R., Hayward, Larry, Hupp, Ted, Sisley, Karen, Huang, Paul H., Carragher, Neil O., Brunton, Valerie G.
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2025
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/412141
Acceso en línea:	http://hdl.handle.net/10261/412141 https://api.elsevier.com/content/abstract/scopus_id/105006831780
Access Level:	acceso abierto
Palabra clave:	Drug screening Patient‐derived xenograft Tumour slices Undifferentiated pleomorphic sarcoma Whole exome sequencing

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oai_identifier_str	oai:digital.csic.es:10261/412141
network_acronym_str	ES
network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
title	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
spellingShingle	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma Manasterski, Piotr Drug screening Patient‐derived xenograft Tumour slices Undifferentiated pleomorphic sarcoma Whole exome sequencing
title_short	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
title_full	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
title_fullStr	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
title_full_unstemmed	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
title_sort	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma
dc.creator.none.fl_str_mv	Manasterski, Piotr Danks, Molly R. Thomson, John P. Muir, Morwenna Lee, Martin Dawson, John C. Amaral, Ana Teresa Diaz-Martin, Juan Moura, David S. Martín-Broto, Javier Alsaadi, Ali Salter, Donald M. Oswald, Ailsa J. Grimes, Graeme R. Hayward, Larry Hupp, Ted Sisley, Karen Huang, Paul H. Carragher, Neil O. Brunton, Valerie G.
author	Manasterski, Piotr
author_facet	Manasterski, Piotr Danks, Molly R. Thomson, John P. Muir, Morwenna Lee, Martin Dawson, John C. Amaral, Ana Teresa Diaz-Martin, Juan Moura, David S. Martín-Broto, Javier Alsaadi, Ali Salter, Donald M. Oswald, Ailsa J. Grimes, Graeme R. Hayward, Larry Hupp, Ted Sisley, Karen Huang, Paul H. Carragher, Neil O. Brunton, Valerie G.
author_role	author
author2	Danks, Molly R. Thomson, John P. Muir, Morwenna Lee, Martin Dawson, John C. Amaral, Ana Teresa Diaz-Martin, Juan Moura, David S. Martín-Broto, Javier Alsaadi, Ali Salter, Donald M. Oswald, Ailsa J. Grimes, Graeme R. Hayward, Larry Hupp, Ted Sisley, Karen Huang, Paul H. Carragher, Neil O. Brunton, Valerie G.
author2_role	author author author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Associazione Italiana per la Ricerca sul Cancro Cancer Research UK Asociación Española Contra el Cáncer Chief Scientist Office (UK) Instituto de Salud Carlos III Medical Research Scotland Sarcoma UK Dawson, John C. [0000-0001-5713-1026] Amaral, Ana Teresa [0000-0001-7887-4814] Moura, David S. [0000-0002-6514-2419] Martín-Broto, Javier [0000-0001-7350-6916] Hupp, Ted [0000-0003-0391-0352] Carragher, Neil O. [0000-0001-5541-9747] Brunton, Valerie G. [0000-0002-7778-8794] Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Drug screening Patient‐derived xenograft Tumour slices Undifferentiated pleomorphic sarcoma Whole exome sequencing
topic	Drug screening Patient‐derived xenograft Tumour slices Undifferentiated pleomorphic sarcoma Whole exome sequencing
description	[Data accessibility] The genomic data generated for patient tumours, cell lines and PDX models presented in this manuscript are currently under upload to the European Genome-Phenome Archive (EGA: https://ega-archive.org/) and will be available upon reasonable request. The WGS reads from UPS samples sequenced in the TCGA Sarcoma project were downloaded in aligned BAM format from the National Cancer Institute Protected Data Cloud Portal (https://portal.gdc.cancer.gov/).
publishDate	2025
dc.date.none.fl_str_mv	2025 2026 2026
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/412141 https://api.elsevier.com/content/abstract/scopus_id/105006831780
url	http://hdl.handle.net/10261/412141 https://api.elsevier.com/content/abstract/scopus_id/105006831780
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1002/1878-0261.70059 https://doi.org/10.1002/1878-0261.70059 Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Wiley-VCH
publisher.none.fl_str_mv	Wiley-VCH
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_	1869417456686071808
spelling	Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcomaManasterski, PiotrDanks, Molly R.Thomson, John P.Muir, MorwennaLee, MartinDawson, John C.Amaral, Ana TeresaDiaz-Martin, JuanMoura, David S.Martín-Broto, JavierAlsaadi, AliSalter, Donald M.Oswald, Ailsa J.Grimes, Graeme R.Hayward, LarryHupp, TedSisley, KarenHuang, Paul H.Carragher, Neil O.Brunton, Valerie G.Drug screeningPatient‐derived xenograftTumour slicesUndifferentiated pleomorphic sarcomaWhole exome sequencing[Data accessibility] The genomic data generated for patient tumours, cell lines and PDX models presented in this manuscript are currently under upload to the European Genome-Phenome Archive (EGA: https://ega-archive.org/) and will be available upon reasonable request. The WGS reads from UPS samples sequenced in the TCGA Sarcoma project were downloaded in aligned BAM format from the National Cancer Institute Protected Data Cloud Portal (https://portal.gdc.cancer.gov/).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.We would like to thank the following service providers at the Institute of Genetics & Cancer, University of Edinburgh; Histology Research Service for sample preparation for IHC, the Advanced Imaging Resource for facilitating the use of microscopes, the Host and Tumour Profiling Unit microarray services for performing RPPA analysis and the Flow Cytometry Facility for running samples and help with data analysis. PHH, JM-B, DSM, PJM, and VGB are members of the International Sarcoma Accelerator Consortium (www.sarcomaaccelerator.org.uk) which was funded by Associazione Italiana per la Ricerca sul Cancro [ID #24297]/Cancer Research UK [C56167/A29363]/Fundacion Científica, Asociacion Espanola Contra el Cancer [Foundation AECC-GEACC19007MA] (to PHH, JM-B, VGB). Additional funding is from Chief Scientist Office [TCS/22/12] (to VGB, JPT, AJO, NOC), Sarcoma UK [SUK07.2022] (to VGB, PHH, AJO) and Sarcoma UK [SUK06.2020] (to VGB, NOC, DMS). DSM is a recipient of a Miguel Servet contract funded by the National Institute of Health Carlos III (ISCIII) (CP24/00131). AJO holds a CRUK/AstraZeneca-funded TRACC clinical research fellowship (C60521/A31343). LH holds an NHS Research Scotland Career Researcher Award.Peer reviewedWiley-VCHAssociazione Italiana per la Ricerca sul CancroCancer Research UKAsociación Española Contra el CáncerChief Scientist Office (UK)Instituto de Salud Carlos IIIMedical Research ScotlandSarcoma UKDawson, John C. [0000-0001-5713-1026]Amaral, Ana Teresa [0000-0001-7887-4814]Moura, David S. [0000-0002-6514-2419]Martín-Broto, Javier [0000-0001-7350-6916]Hupp, Ted [0000-0003-0391-0352]Carragher, Neil O. [0000-0001-5541-9747]Brunton, Valerie G. [0000-0002-7778-8794]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/412141https://api.elsevier.com/content/abstract/scopus_id/105006831780reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1002/1878-0261.70059https://doi.org/10.1002/1878-0261.70059Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4121412026-05-22T06:33:51Z
score	15,81155

Genomics-led approach to drug testing in models of undifferentiated pleomorphic sarcoma

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