Cargando…

Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lima, Nadia Carvalho, Atkinson, Eliza, Bunney, Tom D., Katan, Matilda, Huang, Paul H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246793/
https://www.ncbi.nlm.nih.gov/pubmed/32370101
http://dx.doi.org/10.3390/ijms21093214
_version_ 1783538029552467968
author Lima, Nadia Carvalho
Atkinson, Eliza
Bunney, Tom D.
Katan, Matilda
Huang, Paul H.
author_facet Lima, Nadia Carvalho
Atkinson, Eliza
Bunney, Tom D.
Katan, Matilda
Huang, Paul H.
author_sort Lima, Nadia Carvalho
collection PubMed
description 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
format Online
Article
Text
id pubmed-7246793
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72467932020-06-10 Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations Lima, Nadia Carvalho Atkinson, Eliza Bunney, Tom D. Katan, Matilda Huang, Paul H. Int J Mol Sci Article 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 MDPI 2020-05-01 /pmc/articles/PMC7246793/ /pubmed/32370101 http://dx.doi.org/10.3390/ijms21093214 Text en © 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/).
spellingShingle Article
Lima, Nadia Carvalho
Atkinson, Eliza
Bunney, Tom D.
Katan, Matilda
Huang, Paul H.
Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
title Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
title_full Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
title_fullStr Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
title_full_unstemmed Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
title_short Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
title_sort targeting the src pathway enhances the efficacy of selective fgfr inhibitors in urothelial cancers with fgfr3 alterations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246793/
https://www.ncbi.nlm.nih.gov/pubmed/32370101
http://dx.doi.org/10.3390/ijms21093214
work_keys_str_mv AT limanadiacarvalho targetingthesrcpathwayenhancestheefficacyofselectivefgfrinhibitorsinurothelialcancerswithfgfr3alterations
AT atkinsoneliza targetingthesrcpathwayenhancestheefficacyofselectivefgfrinhibitorsinurothelialcancerswithfgfr3alterations
AT bunneytomd targetingthesrcpathwayenhancestheefficacyofselectivefgfrinhibitorsinurothelialcancerswithfgfr3alterations
AT katanmatilda targetingthesrcpathwayenhancestheefficacyofselectivefgfrinhibitorsinurothelialcancerswithfgfr3alterations
AT huangpaulh targetingthesrcpathwayenhancestheefficacyofselectivefgfrinhibitorsinurothelialcancerswithfgfr3alterations