Comprehensive multi-platform tyrosine kinase profiling reveals novel actionable FGFR aberrations across sarcomas...

Area of Science:

• Oncology
• Genomics
• Pharmacology

Background:

• Limited targeted therapies exist for pediatric sarcomas, with tyrosine kinase (TK) inhibitors showing variable efficacy.
• A key challenge is the lack of predictive biomarkers to guide TK-targeted treatment selection.
• While TK-activating mutations are rare, TK RNA overexpression is common, but its link to pathway activation is unclear.

Purpose of the Study:

• To investigate the TK molecular landscape in pediatric sarcoma patients.
• To identify biomarkers predicting response to TK inhibitors.
• To explore therapeutic strategies targeting TK pathways in sarcomas.

Main Methods:

• Whole genomic and transcriptomic sequencing of 107 pediatric sarcoma patients.
• Phosphoproteomic analysis of tyrosine phosphorylation (pY).
• In vitro and in vivo functional assays using cell lines and patient-derived xenografts (PDXs).

Main Results:

• Novel actionable genomic driver lesions were rare but identified, including an LSM1-FGFR1 fusion in osteosarcoma.
• TK RNA expression can correlate with TK pathway activity and predict inhibitor sensitivity in specific contexts.
• FGFR-inhibitors showed efficacy in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) with high FGFR4/FGF8 expression and FGFR4 activation.

Conclusions:

• Identified actionable genomic alterations in pediatric sarcomas.
• Demonstrated the utility of TK RNA expression as a predictive biomarker for TK inhibitor response.
• Highlighted FGFR-inhibitors as a promising therapeutic strategy for FP-RMS, supported by preclinical and clinical data.