期刊
CANCER DISCOVERY
卷 6, 期 8, 页码 838-851出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-1246
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资金
- Cancer Research UK grant [C30746/A16642]
- NIHR ICR/RMH biomedical research center
- RMH Research fund
- Breast Cancer Now
- Mary-Jean Mitchell Green Foundation
- Cancer Research UK [16642] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10161, NF-SI-0515-10045] Funding Source: researchfish
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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