High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.
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Authors
Pearson, A
Smyth, E
Babina, IS
Herrera-Abreu, MT
Tarazona, N
Peckitt, C
Kilgour, E
Smith, NR
Geh, C
Rooney, C
Cutts, R
Campbell, J
Ning, J
Fenwick, K
Swain, A
Brown, G
Chua, S
Thomas, A
Johnston, SRD
Ajaz, M
Sumpter, K
Gillbanks, A
Watkins, D
Chau, I
Popat, S
Cunningham, D
Turner, NC
Smyth, E
Babina, IS
Herrera-Abreu, MT
Tarazona, N
Peckitt, C
Kilgour, E
Smith, NR
Geh, C
Rooney, C
Cutts, R
Campbell, J
Ning, J
Fenwick, K
Swain, A
Brown, G
Chua, S
Thomas, A
Johnston, SRD
Ajaz, M
Sumpter, K
Gillbanks, A
Watkins, D
Chau, I
Popat, S
Cunningham, D
Turner, NC
Document Type
Journal Article
Date
2016-08-01
Date Accepted
2016-05-09
Abstract
UNLABELLED: 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. Cancer Discov; 6(8); 838-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
Citation
Cancer discovery, 2016, 6 (8), pp. 838 - 851
Rights
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
Research Team
Endocrine Therapy Resistance
Molecular Oncology
Medicine (RMH Smith Cunningham)
Thoracic Oncology
Development & Cancer
Molecular Oncology
Medicine (RMH Smith Cunningham)
Thoracic Oncology
Development & Cancer