Journal Article

Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models

Welm, Alana L., Lim, Elgene, Richardson, Gary, Chew, Nicole J., Swarbrick, Alex, Micati, Diana, Daly, Roger J., Nottle, Tim, Yang, Jessica, Nguyen, Elizabeth V., Hui, Mun N., Lang, Tali, Gregory, Peter, Abud, Helen E., Deng, Niantao, Lim Kam Sian, Terry C. C., Vereker, Melissa, Shin, Sung-Young, Jardé, Thierry, Lee, Rachel S., Kerr, Genevieve, McLean, Catriona A.

2021

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Animals / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer patients / Cancer Research / Cancer therapies / Care and treatment / Chemotherapy / Clinical trials / DNA-Binding Proteins - genetics / Drug development / Extracellular matrix / Fibroblast growth factor receptor / Fibroblast growth factor receptor 1 / Fibroblast growth factor receptor 2 / Fibroblast growth factor receptor 4 / Fibroblast growth factor receptors / Fibroblast growth factors / Gene expression / Humans / Immunohistochemistry / Kinases / Mass spectrometry / Medical prognosis / Metastasis / Mice / Models, Biological / Molecular Targeted Therapy / Mutation / Oncogene / Oncology / Organoids / Organoids - drug effects / Organoids - metabolism / Patients / Peptides / Phosphorylation / Physiological aspects / Precision Medicine / Precision oncology / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein kinases / Protein-tyrosine kinase / Proteins / Proto-Oncogene Proteins - genetics / Receptors, Fibroblast Growth Factor - antagonists & inhibitors / Receptors, Fibroblast Growth Factor - genetics / Receptors, Fibroblast Growth Factor - metabolism / Research Article / RNA sequencing / Scientific equipment and supplies industry / Scientific imaging / SKI proto-oncogene / Sodium / Stroma / Surgical Oncology / Targeted therapy / Therapeutic applications / Therapeutic targets / Transcriptomics / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Tyrosine / Western blotting / Xenograft Model Antitumor Assays / Xenografts