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

P. Pucci, LC. Lee, M. Han, JD. Matthews, L. Jahangiri, M. Schlederer, E. Manners, A. Sorby-Adams, J. Kaggie, RM. Trigg, C. Steel, L. Hare, ER. James, N. Prokoph, SP. Ducray, O. Merkel, F. Rifatbegovic, J. Luo, S. Taschner-Mandl, L. Kenner, GAA....

. 2024 ; 15 (1) : 3422. [pub] 20240423

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc24014269

Grant support
NBUKTurner19 Neuroblastoma UK (NBUK)
16-209 CHILDREN with CANCER UK
C9685/A25117 Cancer Research UK (CRUK)

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.

Center for Biomarker Research in Medicine Graz Austria

Chelsea and Westminster Hospital NHS Foundation Trust London SW10 9NH UK

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Life Sciences Birmingham City University Birmingham UK

Department of Medicine University of Cambridge Addenbrookes Hospital Hills Road Cambridge CB2 0QQ UK

Department of Paediatric Haematology Oncology and Palliative Care Addenbrooke's Hospital Cambridge CB2 0QQ UK

Department of Pathology Division of Cellular and Molecular Pathology University of Cambridge Cambridge CB20QQ UK

Department of Pathology Division of Experimental and Translational Pathology Medical University of Vienna 1090 Vienna Austria

Department of Pathology Medical University of Vienna Vienna 1090 Austria

Department of Radiology University of Cambridge Cambridge Biomedical Campus Cambridge CB2 0QQ UK

European Research Initiative for ALK related malignancies Cambridge CB2 0QQ UK

Faculty of Medicine Masaryk University Brno Czech Republic

Functional Genomics GlaxoSmithKline Stevenage SG1 2NY UK

Laboratory of Cancer Biology and Genetics Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20814 USA

Merck and Co 2000 Galloping Hill Rd Kenilworth NJ 07033 USA

MRC Mitochondrial Biology Unit University of Cambridge The Keith Peters Building Cambridge Biomedical Campus Hills Road Cambridge CB2 0XY UK

Nottingham Trent University School of Science and Technology Clifton Lane Nottingham NG11 8NS UK

OncoSec San Diego CA 92121 USA

St Anna Children's Cancer Research Institute CCRI Zimmermannplatz 10 1090 Vienna Austria

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

References provided by Crossref.org

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