Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/38693
Title: High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.
Authors: Pearson, A.
Smyth, E.
Babina, I. S.
Herrera-Abreu, M. T.
Tarazona, N.
Peckitt, C.
Kilgour, E.
Smith, N. R.
Geh, C.
Rooney, C.
Cutts, R.
Campbell, J.
Ning, J.
Fenwick, K.
Swain, A.
Brown, G.
Chua, S.
Thomas, Anne
Johnston, S. R.
Ajaz, M.
Sumpter, K.
Gillbanks, A.
Watkins, D.
Chau, I.
Popat, S.
Cunningham, D.
Turner, N. C.
First Published: 13-May-2016
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.
DOI Link: 10.1158/2159-8290.CD-15-1246
ISSN: 2159-8274
eISSN: 2159-8290
Links: http://cancerdiscovery.aacrjournals.org/content/6/8/838
http://hdl.handle.net/2381/38693
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
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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