dc.contributor.author | Pearson, A | |
dc.contributor.author | Smyth, E | |
dc.contributor.author | Babina, IS | |
dc.contributor.author | Herrera-Abreu, MT | |
dc.contributor.author | Tarazona, N | |
dc.contributor.author | Peckitt, C | |
dc.contributor.author | Kilgour, E | |
dc.contributor.author | Smith, NR | |
dc.contributor.author | Geh, C | |
dc.contributor.author | Rooney, C | |
dc.contributor.author | Cutts, R | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Ning, J | |
dc.contributor.author | Fenwick, K | |
dc.contributor.author | Swain, A | |
dc.contributor.author | Brown, G | |
dc.contributor.author | Chua, S | |
dc.contributor.author | Thomas, A | |
dc.contributor.author | Johnston, SRD | |
dc.contributor.author | Ajaz, M | |
dc.contributor.author | Sumpter, K | |
dc.contributor.author | Gillbanks, A | |
dc.contributor.author | Watkins, D | |
dc.contributor.author | Chau, I | |
dc.contributor.author | Popat, S | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Turner, NC | |
dc.date.accessioned | 2016-10-14T14:53:13Z | |
dc.date.issued | 2016-08-01 | |
dc.identifier.citation | Cancer discovery, 2016, 6 (8), pp. 838 - 851 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/165 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.cd-15-1246 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 838 - 851 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Breast Neoplasms | |
dc.subject | Stomach Neoplasms | |
dc.subject | Benzamides | |
dc.subject | Piperazines | |
dc.subject | Pyrazoles | |
dc.subject | Tachykinins | |
dc.subject | Receptors, Fibroblast Growth Factor | |
dc.subject | Antineoplastic Agents | |
dc.subject | Positron-Emission Tomography | |
dc.subject | Tomography, X-Ray Computed | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Gene Expression Profiling | |
dc.subject | Signal Transduction | |
dc.subject | Gene Amplification | |
dc.subject | Phosphorylation | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Clonal Evolution | |
dc.title | High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-05-09 | |
rioxxterms.versionofrecord | 10.1158/2159-8290.cd-15-1246 | |
rioxxterms.licenseref.startdate | 2016-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer discovery | |
pubs.issue | 8 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Thoracic Oncology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Thoracic Oncology/Thoracic Oncology (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrine Therapy Resistance | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Thoracic Oncology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Thoracic Oncology/Thoracic Oncology (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 6 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Endocrine Therapy Resistance | |
icr.researchteam | Molecular Oncology | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Thoracic Oncology | |
icr.researchteam | Development & Cancer | |
dc.contributor.icrauthor | Pearson, Alex | |
dc.contributor.icrauthor | Babina, Irina | |
dc.contributor.icrauthor | Cutts, Rosalind | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Swain, Amanda | |
dc.contributor.icrauthor | Turner, Nicholas | |