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dc.contributor.authorLima, NC
dc.contributor.authorAtkinson, E
dc.contributor.authorBunney, TD
dc.contributor.authorKatan, M
dc.contributor.authorHuang, PH
dc.date.accessioned2020-05-19T10:43:37Z
dc.date.issued2020-05
dc.identifier.citationInternational journal of molecular sciences, 2020, 21 (9)
dc.identifier.issn1422-0067
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3615
dc.identifier.eissn1422-0067
dc.identifier.doi10.3390/ijms21093214
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.
dc.formatElectronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleTargeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations.
dc.typeJournal Article
dcterms.dateAccepted2020-04-27
rioxxterms.versionofrecord10.3390/ijms21093214
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfInternational journal of molecular sciences
pubs.issue9
pubs.notesNo embargo
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.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-statusPublished
pubs.volume21
pubs.embargo.termsNo embargo
icr.researchteamMolecular and Systems Oncologyen_US
dc.contributor.icrauthorHuang, Paulen


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