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

Lookup NU author(s): Dr Kate Sumpter

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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. (C) 2016 AACR.

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Author(s): 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

Publication type: Article

Publication status: Published

Journal: Cancer Discovery

Year: 2016

Volume: 6

Issue: 8

Pages: 838-851

Print publication date: 01/08/2016

Online publication date: 01/08/2016

Acceptance date: 09/05/2016

ISSN (print): 2159-8274

ISSN (electronic): 2159-8290

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/2159-8290.CD-15-1246

DOI: 10.1158/2159-8290.CD-15-1246

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