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|Title:||High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.|
Babina, I. S.
Herrera-Abreu, M. T.
Smith, N. R.
Johnston, S. R.
Turner, N. C.
|Publisher:||American Association for Cancer Research|
|Citation:||Cancer Discovery, 2016, 6 (8), pp. 838-851|
|Abstract:||FGFR1 and FGFR2 are amplified in many tumor 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, whereas cancers with subclonal or low-level amplification did not respond. Using cell lines and patient-derived xenograft models, we show that high-level FGFR2 amplification initiates a distinct oncogene addiction phenotype, characterized by FGFR2-mediated transactivation of alternative receptor kinases, bringing PI3K/mTOR signaling under FGFR control. Signaling in low-level FGFR1-amplified cancers is more restricted to MAPK signaling, limiting sensitivity to FGFR inhibition. Finally, we show that circulating tumor DNA screening can identify high-level clonally amplified cancers. Our data provide 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. Significance: Robust single-agent response to FGFR inhibition is seen only in high-level FGFR-amplified cancers, with copy-number level dictating response to FGFR inhibition 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 tumor DNA may present a viable strategy to screen patients.|
|Rights:||©2016 American Association for Cancer Research. Archived with reference to SHERPA/RoMEO and publisher website.|
|Description:||Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).|
|Appears in Collections:||Published Articles, Dept. of Cancer Studies and Molecular Medicine|
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|Pearsonetal2015_ Figs_SuppFigs.pdf||Post-review (final submitted author manuscript)||25.56 MB||Adobe PDF||View/Open|
|2015 Pearson et al main text_Final_clean v3.pdf||Post-review (final submitted author manuscript)||466.66 kB||Adobe PDF||View/Open|
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