1/1
2 files

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

journal contribution
posted on 23.11.2016, 15:03 by 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, J. Ning, K. Fenwick, A. Swain, G. Brown, S. Chua, Anne Thomas, S. R. Johnston, M. Ajaz, K. Sumpter, A. Gillbanks, D. Watkins, I. Chau, S. Popat, D. Cunningham, N. C. Turner
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.

Funding

This research has been supported by Cancer Research UK grant C30746/A16642. N.C. Turner acknowledges generous support from both Breast Cancer Now and the Mary-Jean Mitchell Green Foundation. E. Smyth, G. Brown, S. Chua, I. Chau, S. Popat, D. Cunningham, and N.C. Turner acknowledge the support of the NIHR ICR/RMH biomedical research center. The authors acknowledge the generous donation of the Birk and Katri families to the RMH Research fund.

History

Citation

Cancer Discovery, 2016, 6 (8), pp. 838-851

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

AM (Accepted Manuscript)

Published in

Cancer Discovery

Publisher

American Association for Cancer Research

issn

2159-8274

eissn

2159-8290

Acceptance date

09/05/2016

Copyright date

2016

Available date

13/05/2017

Publisher version

http://cancerdiscovery.aacrjournals.org/content/6/8/838

Notes

Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

Language

en

Usage metrics

Categories

Keywords

Exports