High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

A. Pearson, E. Smyth, I. S. Babina, M. T. Herrera-Abreu, N. Tarazona, C. Peckitt, E. Kilgour, N. R. Smith, C. Geh, C. Rooney, R. Cutts, J. Campbell (+15 others)
2016 Cancer Discovery  
FGFR1 and FGFR2 are amplified in many tumour types, yet what determines response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial we show that gastric cancers with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR inhibitor AZD4547, whilst cancers with sub-clonal or low-level amplification did not respond. Using cell lines and patient derived xenografts models, we show high-level FGFR2 amplification initiates a distinct
more » ... ogene addiction phenotype, characterised by FGFR2 mediated transactivation of alternative receptor kinases, bringing PI3 kinase/mTOR signalling under FGFR control. Signalling in low-level FGFR1 amplified cancers is more restricted to MAPK signalling, limiting sensitivity to FGFR inhibition. Finally, we show circulating tumour DNA screening can identify high-level clonally amplified cancers. Our data provides a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly-amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy. Statement of Significance Robust single agent response is only seen in high-level FGFR amplified cancers, with copy number level dictating response to FGFR inhibition both in vitro, in vivo, and in the clinic. High-level amplification of FGFR2 is relatively rare in gastric and breast cancers, and we show that screening for amplification in circulating tumour DNA may present a viable strategy to screen patients.
doi:10.1158/2159-8290.cd-15-1246 pmid:27179038 pmcid:PMC5338732 fatcat:razilydc4jclnfu5p4t62lnnbm