Comprehensive Multiplatform Tyrosine Kinase Profiling Reveals Novel Actionable FGFR Aberrations across Sarcomas Affecting the Young
Year: 2026
Type: article
Abstract: Limited targeted agents are approved for pediatric sarcomas. Tyrosine kinase (TK) inhibitors (TKi) have shown clinical efficacy in some, but not all, young patients with sarcoma. A major obstacle preventing further advances and clinical implementation is the lack of predictive response biomarkers to guide TK-targeted treatments. TK-activating fusions or mutations are rare in these patients. RNA overexpression of TKs is a frequent feature. The unresolved question is when upregulated TK expression is associated with kinase activation and signaling dependence. We explored the TK molecular landscape of 107 patients with sarcoma from the ZERO Childhood Cancer Precision Medicine Program (ZERO) using whole-genome and -transcriptome sequencing. Phosphoproteomic analyses of tyrosine phosphorylation (pY) and functional in vitro and in vivo assays were performed in cell lines and patient-derived xenografts (PDX). Our analysis shows that although novel genomic driver lesions are rare, when present they are therapeutically actionable as exemplified by a novel LSM1-FGFR1 fusion identified in a patient with osteosarcoma. We further show that in certain contexts, TK RNA expression can indicate TK pathway activity and predict TKi sensitivity. We highlight the utility of FGFR inhibitors in PAX3-FOXO1 fusion-positive rhabdomyosarcomas (FP-RMS) characterized by high FGFR4 and FGF8 RNA expression levels and FGFR4 activation (FGFR4_pY). We demonstrate marked tumor growth inhibition in all FP-RMS PDXs treated with single-agent FGF401 (FGFR4-specific inhibitor) and single-agent lenvatinib (multikinase FGFR inhibitor) and report a clinical response to lenvatinib in a patient with relapsed metastatic FP-RMS. Altogether, we identified new patients with sarcoma who may benefit from FGFR inhibitors, most notably FP-RMS via FGFR4/FGF8 coexpression.
Source: Molecular Cancer Therapeutics
Authors: Ashleigh M. Fordham, Lauren M. Brown, Chelsea Mayoh, Alice Salib, Zara A. Barger, Marie Wong, Terry C.C. Lim Kam Sian, Changyuan Hu, Jinhan Xie, Kate Gunther, Peter Trebilcock, Rachael L. Terry, Paulette Barahona, Pamela Ajuyah, Alexandra Sherstyuk, Anica Avila, Roxanne Cadiz, Callum M. Perkins, Andrew J. Gifford, Jie Mao, M. Emmy M. Dolman, Andrea Zhao, Luke P. O’Regan, Daniel Gorgels, Loretta M.S. Lau, David S. Ziegler, Michelle Haber, Vanessa Tyrrell, Richard B. Lock, Mark J. Cowley, Wayne Nicholls, Roger J. Daly, Paul G. Ekert, Emmy D.G. Fleuren
Institutions: UNSW Sydney, Monash University, Wenzhou Medical University, Prince of Wales Hospital, NSW Health Pathology, Sydney Children's Hospital, The University of Queensland, Children's Health Queensland Hospital and Health Service, Royal Children's Hospital, Peter MacCallum Cancer Centre, Murdoch Children's Research Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Award: G3758782176
OpenAlex ID: W7138856118