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High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial
Alex Pearson1, Elizabeth Smyth2, Irina S Babina1
1The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
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.
Insights
High-level FGFR2 amplification in gastric cancer predicts response to FGFR inhibitors like AZD4547. This study reveals FGFR amplification clonality is key for targeted therapy success and identifies circulating tumor DNA as a screening tool.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fibroblast Growth Factor Receptor (FGFR) amplification occurs in various cancers.
- The determinants of response to FGFR inhibition in amplified cancers remain unclear.
Purpose of the Study:
- To investigate the relationship between FGFR amplification levels and response to FGFR inhibitors.
- To elucidate the molecular mechanisms underlying differential sensitivity to FGFR inhibition.
- To assess the utility of circulating tumor DNA (ctDNA) for identifying patients eligible for FGFR-targeted therapy.
Main Methods:
- Translational clinical trial involving FGFR inhibitor AZD4547.
- Analysis of gastric cancer cell lines and patient-derived xenograft models.
- Assessment of FGFR amplification clonality and copy-number levels.
- Evaluation of downstream signaling pathways (PI3K/mTOR, MAPK).
- Circulating tumor DNA screening.
Main Results:
- High-level clonal FGFR2 amplification in gastric cancer correlated with a high response rate to AZD4547.
- Low-level or subclonal amplifications did not confer sensitivity to FGFR inhibition.
- High-level FGFR2 amplification drives oncogene addiction via FGFR2-mediated transactivation of alternative receptor kinases, engaging PI3K/mTOR signaling.
- Low-level FGFR1 amplification primarily impacts MAPK signaling, limiting sensitivity.
- ctDNA screening effectively identified patients with high-level clonal amplification.
Conclusions:
- FGFR amplification clonality dictates sensitivity to FGFR inhibitors, with high-level amplification establishing a distinct oncogene addiction phenotype.
- Targeted therapy response is dependent on the precise level and clonality of FGFR amplification.
- ctDNA screening offers a viable strategy for patient selection in FGFR-targeted therapies.
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