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Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma
Priya Chudasama1, Marcus Renner2, Melanie Straub3
1Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway.Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962-73. ©2016 AACR.
Insights
Fibroblast growth factor receptor 1 (FGFR1) is a driver gene in soft-tissue sarcoma (STS). FGFR1 inhibition is a potential therapeutic option for STS patients, guided by FGFR1 expression and MAPK-ERK1/2 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Altered fibroblast growth factor receptor 1 (FGFR1) signaling is a therapeutic target in epithelial cancers.
- The role of FGFR1 in soft-tissue sarcoma (STS) was previously undefined.
Purpose of the Study:
- Investigate the oncogenic properties of FGFR1 in STS.
- Determine the potential of FGFR1 as a drug target in STS patients.
Main Methods:
- Assessed FGFR1 amplification and overexpression in three STS patient cohorts using FISH, SNP array, and RNA sequencing.
- Evaluated STS cell line sensitivity to FGFR1 inhibition (genetic and pharmacologic).
- Analyzed FGFR1-engaged signaling pathways via viability and colony formation assays.
Main Results:
- FGFR1 amplification detected in 31.5–38.9% of STS patients across cohorts.
- FGFR1 overexpression observed in 15.4–20.2% of STS patients.
- FGFR1 inhibition efficacy correlated with FGFR1 expression levels; MAPK-ERK1/2 identified as a key effector pathway.
Conclusions:
- FGFR1 is a driver gene in multiple STS subtypes.
- FGFR1 inhibition presents a viable therapeutic strategy for STS.
- Patient selection based on FGFR1 expression and MAPK-ERK1/2 signaling monitoring is recommended.
