High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.
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Date
2016-08-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Animals
Humans
Mice
Breast Neoplasms
Stomach Neoplasms
Benzamides
Piperazines
Pyrazoles
Tachykinins
Receptors, Fibroblast Growth Factor
Antineoplastic Agents
Positron-Emission Tomography
Tomography, X-Ray Computed
Xenograft Model Antitumor Assays
Gene Expression Profiling
Signal Transduction
Gene Amplification
Phosphorylation
Female
Male
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Molecular Targeted Therapy
Clonal Evolution
Research team
Endocrine Therapy Resistance
Molecular Oncology
Medicine (RMH Smith Cunningham)
Thoracic Oncology
Development & Cancer
Language
eng
Date accepted
2016-05-09
License start date
2016-08
Citation
Cancer discovery, 2016, 6 (8), pp. 838 - 851
Publisher
AMER ASSOC CANCER RESEARCH