eprintid: 10097692 rev_number: 14 eprint_status: archive userid: 608 dir: disk0/10/09/76/92 datestamp: 2020-05-19 13:37:52 lastmod: 2021-10-06 22:43:51 status_changed: 2020-05-19 13:37:52 type: article metadata_visibility: show creators_name: Lima, NC creators_name: Atkinson, E creators_name: Bunney, TD creators_name: Katan, M creators_name: Huang, PH title: Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations ispublished: pub divisions: UCL divisions: B02 divisions: C08 divisions: D09 divisions: G03 keywords: FGFR3; Src; urothelial cancer; bladder cancer; cell signalling; cancer therapeutics note: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). abstract: Selective 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 date: 2020-05-01 date_type: published official_url: https://doi.org/10.3390/ijms21093214 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1781824 doi: 10.3390/ijms21093214 pii: ijms21093214 lyricists_name: Bunney, Tom lyricists_name: Katan, Matilda lyricists_id: TBUNN06 lyricists_id: MKATA81 actors_name: Kalinowski, Damian actors_id: DKALI47 actors_role: owner full_text_status: public publication: International Journal of Molecular Sciences volume: 21 number: 9 article_number: 3214 event_location: Switzerland citation: Lima, NC; Atkinson, E; Bunney, TD; Katan, M; Huang, PH; (2020) Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations. International Journal of Molecular Sciences , 21 (9) , Article 3214. 10.3390/ijms21093214 <https://doi.org/10.3390/ijms21093214>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10097692/1/Bunney_Targeting%20the%20Src%20Pathway%20Enhances%20the%20Efficacy%20of%20Selective%20FGFR%20Inhibitors%20in%20Urothelial%20Cancers%20with%20FGFR3%20Alterations_VoR.pdf