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dc.contributor.authorLima, NCen_US
dc.contributor.authorAtkinson, Een_US
dc.contributor.authorBunney, TDen_US
dc.contributor.authorKatan, Men_US
dc.contributor.authorHuang, PHen_US
dc.date.accessioned2020-05-19T10:43:37Z
dc.date.issued2020-05en_US
dc.identifier.citationInternational journal of molecular sciences, 2020, 21 (9)en_US
dc.identifier.issn1422-0067en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3615
dc.identifier.eissn1422-0067en_US
dc.identifier.doi10.3390/ijms21093214en_US
dc.description.abstractSelective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations.en_US
dc.formatElectronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleTargeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-04-27en_US
rioxxterms.versionofrecord10.3390/ijms21093214en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2020-05en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfInternational journal of molecular sciencesen_US
pubs.issue9en_US
pubs.notesNo embargoen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular and Systems Oncology
pubs.publication-statusPublisheden_US
pubs.volume21en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMolecular and Systems Oncologyen_US
dc.contributor.icrauthorHuang, Paulen_US


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