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

Nadia Carvalho Lima,Matilda Katan,Eliza Atkinson,Tom D Bunney,Paul H Huang

doi:10.3390/ijms21093214

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

Highlights

Activating molecular alterations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene have been identified through large-scale generation genomic sequencing efforts across a range of tumour types including urothelial carcinoma, lung squamous cell carcinoma, glioblastoma and myeloma [1,2,3,4]
Constitutive activation of Src was associated with the expression of the FGFR3 mutants and FGFR3-TACC3 fusion in the NIH-3T3 cells (Figure 1A), the phosphorylation levels of Src were not downregulated upon FGFR3 kinase inhibition by infigratinib (Figure 1F)
We use a combination of NIH-3T3 and urothelial cancer cells to demonstrate that cells expressing a subset of FGFR3 molecular alterations co-opt the Src pathway to promote intrinsic resistance to selective FGFR inhibitors

Summary

Introduction

Activating molecular alterations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene have been identified through large-scale generation genomic sequencing efforts across a range of tumour types including urothelial carcinoma, lung squamous cell carcinoma, glioblastoma and myeloma [1,2,3,4]. The BLC2001 phase II single-arm trial of erdafitinib in FGFR-altered urothelial carcinomas showed clinical responses in 40% of patients [14] This result has led to the accelerated approval of erdafitinib in 2019 by the US Food and Drug Administration (FDA) for locally advanced or metastatic urothelial carcinomas with FGFR2 and FGFR3 alterations. Pal et al, reported that only 42.9% of patients with documented FGFR3 activating point mutations responded to infigratinib [13,14] These results indicate that notwithstanding the presence of a FGFR3 molecular alteration, there remains a significant proportion of patients that harbour intrinsic resistance to selective FGFR TKIs and do not respond to these agents. There are limited therapeutic alternatives available and there is an urgent unmet need to identify effective ways to overcome primary resistance

Methods

Results

Conclusion