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Cancer Discov. 2016 Aug;6(8):838-851. doi: 10.1158/2159-8290.CD-15-1246. Epub 2016 May 13.

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

Author information

1
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
2
GI Unit, Royal Marsden Hospital, London, UK.
3
AstraZeneca Oncology, Cheshire, UK.
4
The Tumour Profiling Unit, Institute of Cancer Research, London, UK.
5
Department of Diagnostic Imaging, The Royal Marsden, Surrey, UK.
6
Nuclear Medicine and PET/CT Department, The Royal Marsden, Surrey, UK.
7
Leicester Royal Infirmary, Leicester, UK.
8
Breast Unit, The Royal Marsden Hospital, London, UK.
9
The Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.
10
Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
11
Lung Unit, The Royal Marsden, London, UK.
#
Contributed equally

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. Cancer Discov; 6(8); 838-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

PMID:
27179038
PMCID:
PMC5338732
DOI:
10.1158/2159-8290.CD-15-1246
[Indexed for MEDLINE]
Free PMC Article

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