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|Ref Type||Journal Article|
|Authors||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 SR, Ajaz M, Sumpter K, Gillbanks A, Watkins D, Chau I, Popat S, Cunningham D, Turner NC|
|Title||High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial.|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR2 amp||stomach cancer||sensitive||AZD4547||Phase II||Actionable||In a Phase II clinical trial, treatment with AZD4547 resulted in a 33% (3/9) response rate in patients with FGFR2-amplified gastroesophageal cancer, and high-level amplification was associated with clinical response (PMID: 27179038).||27179038|
|FGFR1 amp||breast cancer||no benefit||AZD4547||Phase II||Actionable||In a Phase II clinical trial, treatment with AZD4547 resulted in a response rate of 12.5% (1/8) in patients with FGFR1-amplified breast cancer, and did not meet the predetermined criteria for efficacy (PMID: 27179038).||27179038|
|FGFR2 amp||stomach cancer||sensitive||PD173074||Preclinical - Cell culture||Actionable||In a preclinical study, FGFR2-amplified gastric cancer cell lines demonstrated sensitivity to PD173074 in culture, with cell lines with high-level FGFR2 amplification displaying higher sensitivity compared to cell lines with low-level amplification (PMID: 27179038).||27179038|