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

Autor: Chew NJ; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia., Lim Kam Sian TCC; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia., Nguyen EV; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia., Shin SY; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia., Yang J; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia., Hui MN; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia., Deng N; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia., McLean CA; Anatomical Pathology, Alfred Hospital, Prahran, VIC, 3004, Australia., Welm AL; Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA., Lim E; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia.; St Vincent's Hospital, Darlinghurst, NSW, 2010, Australia., Gregory P; Cabrini Health, Brighton, VIC, 3186, Australia., Nottle T; TissuPath, Mount Waverley, VIC, 3149, Australia., Lang T; Szalmuk Family Department of Medical Oncology, Cabrini Institute, Malvern, VIC, 3144, Australia., Vereker M; Szalmuk Family Department of Medical Oncology, Cabrini Institute, Malvern, VIC, 3144, Australia., Richardson G; Szalmuk Family Department of Medical Oncology, Cabrini Institute, Malvern, VIC, 3144, Australia., Kerr G; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia., Micati D; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia., Jardé T; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia., Abud HE; Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia., Lee RS; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia., Swarbrick A; Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia., Daly RJ; Cancer Program, Monash Biomedicine Discovery Institute, Clayton, VIC, 3800, Australia. roger.daly@monash.edu.; Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia. roger.daly@monash.edu.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2021 Aug 03; Vol. 23 (1), pp. 82. Date of Electronic Publication: 2021 Aug 03.
DOI: 10.1186/s13058-021-01461-4
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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