Evaluation of the Role of AXL in Fusion-positive Pediatric Rhabdomyosarcoma Identifies the Small-molecule Inhibitor Bemcentinib (BGB324) as Potent Chemosensitizer.

Autor:	Danielli SG; Department of Oncology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland., Wurth J; Department of Oncology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland., Morice S; Balgrist University Hospital, Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland., Kisele S; Department of Oncology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland., Surdez D; Balgrist University Hospital, Faculty of Medicine, University of Zürich (UZH), Zürich, Switzerland.; INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Laboratory, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France., Delattre O; INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Laboratory, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France., Bode PK; Department of Pathology, University Hospital Zürich, Zürich, Switzerland., Wachtel M; Department of Oncology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland., Schäfer BW; Department of Oncology and Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Jun 04; Vol. 23 (6), pp. 864-876.
DOI:	10.1158/1535-7163.MCT-23-0285
Abstrakt:	Rhabdomyosarcoma (RMS) is a highly aggressive pediatric cancer with features of skeletal muscle differentiation. More than 80% of the high-risk patients ultimately fail to respond to chemotherapy treatment, leading to limited therapeutic options and dismal prognostic rates. The lack of response and subsequent tumor recurrence is driven in part by stem cell-like cells, the tumor subpopulation that is enriched after treatment, and characterized by expression of the AXL receptor tyrosine kinase (AXL). AXL mediates survival, migration, and therapy resistance in several cancer types; however, its function in RMS remains unclear. In this study, we investigated the role of AXL in RMS tumorigenesis, migration, and chemotherapy response, and whether targeting of AXL with small-molecule inhibitors could potentiate the efficacy of chemotherapy. We show that AXL is expressed in a heterogeneous manner in patient-derived xenografts (PDX), primary cultures and cell line models of RMS, consistent with its stem cell-state selectivity. By generating a CRISPR/Cas9 AXL knock-out and overexpressing models, we show that AXL contributes to the migratory phenotype of RMS, but not to chemotherapy resistance. Instead, pharmacologic blockade with the AXL inhibitors bemcentinib (BGB324), cabozantinib and NPS-1034 rapidly killed RMS cells in an AXL-independent manner and augmented the efficacy of the chemotherapeutics vincristine and cyclophosphamide. In vivo administration of the combination of bemcentinib and vincristine exerted strong antitumoral activity in a rapidly progressing PDX mouse model, significantly reducing tumor burden compared with single-agent treatment. Collectively, our data identify bemcentinib as a promising drug to improve chemotherapy efficacy in patients with RMS. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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