High-level clonal FGFR amplification are response to FGFR inhibition in a translational clinical trial

FGFR1 and FGFR2 are amplified in many tumour types, yet what may determine response to FGFR inhibition in amplified cancers is unknown. In a translational clinical trial we show that gastric cancers with high-level and 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 cancer cell lines and patient derived xenografts models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterised by FGFR2 mediated transactivation of alternative receptor kinases, resulting in PI3 kinase and mTOR signaling becoming FGFR dependent