%D 2020
%T Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations
%V 21
%A NC Lima
%A E Atkinson
%A TD Bunney
%A M Katan
%A PH Huang
%N 9
%C Switzerland
%X 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
%O © 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/).
%K FGFR3; Src; urothelial cancer; bladder cancer; cell signalling; cancer therapeutics
%J International Journal of Molecular Sciences
%L discovery10097692