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Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

Pucci, Perla
Author Pucci, Perla ORCID Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK
Lee, Liam C
Author Lee, Liam C Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK Merck & Co, 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA
Han, Miaojun
Author Han, Miaojun Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK OncoSec, San Diego, CA, 92121, USA
Matthews, Jamie D
Author Matthews, Jamie D ORCID Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK
Jahangiri, Leila
Author Jahangiri, Leila Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK Department of Life Sciences, Birmingham City University, Birmingham, UK Nottingham Trent University, School of Science & Technology, Clifton Lane, Nottingham, NG11 8NS, UK
Schlederer, Michaela
Author Schlederer, Michaela Department of Pathology, Division of Experimental and Translational Pathology, Medical University of Vienna, 1090, Vienna, Austria
Manners, Eleanor
Author Manners, Eleanor Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK Chelsea and Westminster Hospital, NHS Foundation Trust, London, SW10 9NH, UK
Sorby-Adams, Annabel
Author Sorby-Adams, Annabel MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK Department of Medicine, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, CB2 0QQ, UK
Kaggie, Joshua
Author Kaggie, Joshua ORCID Department of Radiology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
Trigg, Ricky M
Author Trigg, Ricky M Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK Functional Genomics, GlaxoSmithKline, Stevenage, SG1 2NY, UK

Nature communications. 2024 Apr 23 ; 15 (1) : 3422. [epub] 20240423

Nat Commun
ISSN 2041-1723
Source

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

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