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

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-thr...

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Published in:	Nature communications Vol. 15; no. 1; p. 3422
Main Authors:	Pucci, Perla, Lee, Liam C., Han, Miaojun, Matthews, Jamie D., Jahangiri, Leila, Schlederer, Michaela, Manners, Eleanor, Sorby-Adams, Annabel, Kaggie, Joshua, Trigg, Ricky M., Steel, Christopher, Hare, Lucy, James, Emily R., Prokoph, Nina, Ducray, Stephen P., Merkel, Olaf, Rifatbegovic, Firkret, Luo, Ji, Taschner-Mandl, Sabine, Kenner, Lukas, Burke, G. A. Amos, Turner, Suzanne D.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-04-2024 Nature Publishing Group Nature Portfolio
Subjects:	13 13/106 13/2 13/31 13/44 38 38/109 38/39 38/77 42 49 59 59/57 631/67/1059 631/67/1059/2326 631/67/2332 64 64/60 82/51 82/80 Anaplastic Lymphoma Kinase - antagonists & inhibitors Anaplastic Lymphoma Kinase - genetics Anaplastic Lymphoma Kinase - metabolism Animals Apoptosis Apoptosis - drug effects Apoptosis - genetics Cell Line, Tumor Cell viability Combined treatment CRISPR Dibenzocycloheptenes Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Drug Synergism Farnesyltransferase Farnesyltranstransferase - antagonists & inhibitors Farnesyltranstransferase - metabolism Female Gene Expression Regulation, Neoplastic - drug effects Genomes GTP Phosphohydrolases - genetics GTP Phosphohydrolases - metabolism Humanities and Social Sciences Humans Inhibitors Kinases Lymphoma Malignancy Membrane Proteins - genetics Membrane Proteins - metabolism Mice MicroRNAs - genetics MicroRNAs - metabolism miRNA multidisciplinary Mutation Neuroblastoma Neuroblastoma - drug therapy Neuroblastoma - genetics Neuroblastoma - metabolism Neuroblastoma - pathology Neuroblasts Piperidines - pharmacology Piperidines - therapeutic use Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Protein-tyrosine kinase Pyridines - pharmacology Pyridines - therapeutic use Science Science (multidisciplinary) Sensitivity Strategy Tumors Tyrosine Tyrosine kinase inhibitors Xenograft Model Antitumor Assays Xenotransplantation
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Summary:	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. Targeting oncogenic ALK activity in neuroblastoma is an attractive therapeutic strategy but success has been limited by resistance to ALK inhibitors. Here, the authors identify loss of miR-1304-5p as a driver of ALK inhibitor resistance via regulation of NRAS, and therapeutically target this axis with the addition of a farnesyltransferase inhibitor in preclinical models of neuroblastoma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-47771-x