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Updated: Oct 25, 2025
Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models
Nicole J Chew1,2, Terry C C Lim Kam Sian1,2, Elizabeth V Nguyen1,2
1Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.
Background:
Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor-stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs.
Methods:
MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival.
Results:
Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated 'omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target.
Conclusions:
This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.
Insights
Patient-derived breast cancer models reveal fibroblast growth factor receptors (FGFRs) as promising therapeutic targets. Specific FGFR inhibitors show efficacy, particularly FGFR4, offering new precision treatment avenues for challenging breast cancer subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Specific breast cancer subtypes present treatment challenges due to limited targeted therapies.
- Patient-derived xenografts (PDX) and organoids (PDO) offer superior pre-clinical models over cell lines, preserving tumor heterogeneity and architecture.
- This study focused on identifying therapeutic targets, especially fibroblast growth factor receptors (FGFRs), using an integrated multi-omic approach in breast cancer PDX and PDO models.
Purpose of the Study:
- To identify novel therapeutic targets in challenging breast cancer subtypes.
- To investigate the role of fibroblast growth factor receptors (FGFRs) in breast cancer progression and drug response.
- To evaluate the efficacy of specific FGFR inhibitors in patient-derived models.
Main Methods:
- Utilized MS-based phosphoproteomics, RNAseq, whole exome sequencing (WES), and Western blotting to analyze kinase activation and drug effects.
- Treated PDX and PDO models with selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4).
- Assessed FGFR4 expression via immunohistochemistry and interrogated public datasets (METABRIC, TCGA) for FGFR alterations and their clinical associations.
Main Results:
- Phosphoproteomic profiling revealed heterogeneous kinase activation, with a subset of PDX models showing enhanced FGFR1, FGFR2, or FGFR4 phosphorylation.
- Identified a novel FGFR2-SKI fusion in a triple-negative breast cancer (TNBC) PDX sensitive to AZD4547, and demonstrated tumor growth inhibition with BLU9931 in an FGFR4-driven luminal B PDX.
- Confirmed on-target drug effects and identified novel impacts on spliceosome, metabolism, and immune signaling pathways; public data analysis linked FGFR alterations to poor prognosis across breast cancer subtypes.
Conclusions:
- Patient-derived models are powerful tools for identifying therapeutic targets and analyzing drug mechanisms in breast cancer.
- Specific fibroblast growth factor receptors (FGFRs), particularly FGFR4, represent promising targets for precision breast cancer therapy.
- This research supports the development of FGFR-targeted therapies for breast cancer patients with specific genetic alterations.
