1562P - Mechanisms of acquired resistance to the fibroblast growth factor receptor (FGFR) inhibitor BGJ398 in FGFR driven bladder cancer

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Presenter Margeaux Hodgson-Garms
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors M. Hodgson-Garms, J. Mariadason, A. Weickhardt
  • Olivia Newton-john Cancer Research Institute, Latrobe University School of Cancer Medicine, 3084 - Melbourne/AU

Abstract

Background

Mutations and fusions of the FGFR3 gene occur in 10-20% of metastatic urothelial carcinoma (mUC), and recent in-vitro work demonstrates that these alterations confer sensitivity to FGFR inhibitors such as BGJ398 (Novartis). Based on these findings a phase I/II clinical trial of BGJ398 in patients with mUC harboring FGFR3 mutations and fusions is underway. The objective of this study was to assess potential mechanisms of acquired resistance to FGFR inhibition in order to develop rational combination therapies to enhance the efficacy of these agents.

Methods

Acquired resistance to the FGFR inhibitor BGJ398 was generated by continuous exposure of the FGFR3 fusion harboring cell lines RT4 and SW780 cells to increasing concentrations of BGJ398. Alterations in cell signaling components and gene expression between parental and resistant cells were assessed by western blots, phospho-kinome arrays, and qRT-PCR. Reversal of drug resistance was assessed by withdrawal of drug from resistant lines and monitoring of cell proliferation.

Results

Acquired resistance to BGJ398 in RT4 and SW780 was associated with morphological changes consistent with epithelial to mesenchymal transition. Consistent with these changes, increased mRNA expression of the mesenchymal markers Vimentin and ZEB1 and loss of expression of the epithelial marker E-Cadherin was observed in resistant cell lines. In both cell lines resistance was accompanied by an increase in pErbB3 and a corresponding increase in expression of the ErbB3 ligand, NRG1. Additionally, resistant cell lines demonstrated an increase in pAXL levels and increased expression of Fra1 mRNA, a transcriptional activator of AXL and known EMT driver. Resistant cell lines were cross resistant to alternative FGFR inhibitors such as PD173074 (Pfizer). Resistant cell lines rapidly regained sensitivity to BGJ398 after drug withdrawal of 1 month.

Conclusions

Acquired resistance to BGJ398 is associated with acquisition of an EMT phenotype, increased pErbB3 and NRG1 expression, and increased expression of the EMT drivers Fra1 and pAXL. Preclinical study of concurrent inhibition of these pathways is underway to assess potential strategies to overcome resistance to FGFR inhibition.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

Grant funding from Pfizer. BGJ398 provided by Novartis

Disclosure

A. Weickhardt: BGJ398 provided by Novartis. Research grant funding provided by Pfizer. All other authors have declared no conflicts of interest.