title: High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.
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.
  
  
  
  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.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Pearson
authors.affiliation: GI Unit, Royal Marsden Hospital, London, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smyth
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Irina S
authors.initials: IS
authors.lastname: Babina
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Herrera-Abreu
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Noelia
authors.initials: N
authors.lastname: Tarazona
authors.affiliation: GI Unit, Royal Marsden Hospital, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: AstraZeneca Oncology, Cheshire, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Kilgour
authors.affiliation: AstraZeneca Oncology, Cheshire, UK.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smith
authors.affiliation: AstraZeneca Oncology, Cheshire, UK.
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authors.lastname: Geh
authors.affiliation: AstraZeneca Oncology, Cheshire, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Rooney
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Ros
authors.initials: R
authors.lastname: Cutts
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Jian
authors.initials: J
authors.lastname: Ning
authors.affiliation: The Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.affiliation: The Tumour Profiling Unit, Institute of Cancer Research, London, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Swain
authors.affiliation: Department of Diagnostic Imaging, The Royal Marsden, Surrey, UK.
authors.forename: Gina
authors.initials: G
authors.lastname: Brown
authors.affiliation: Nuclear Medicine and PET/CT Department, The Royal Marsden, Surrey, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Chua
authors.affiliation: Leicester Royal Infirmary, Leicester, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Breast Unit, The Royal Marsden Hospital, London, UK.
authors.forename: Stephen R D
authors.initials: SRD
authors.lastname: Johnston
authors.affiliation: The Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.
authors.forename: Mazhar
authors.initials: M
authors.lastname: Ajaz
authors.affiliation: Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Sumpter
authors.affiliation: GI Unit, Royal Marsden Hospital, London, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Gillbanks
authors.affiliation: GI Unit, Royal Marsden Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: GI Unit, Royal Marsden Hospital, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
authors.affiliation: Lung Unit, The Royal Marsden, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: GI Unit, Royal Marsden Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.|Breast Unit, The Royal Marsden Hospital, London, UK.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D060965:Clonal Evolution / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D015320:Tachykinins / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor; D015320:Tachykinins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt