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

Perla Pucci, Liam C. Lee, Miaojun Han, Jamie D. Matthews, Leila Jahangiri, Michaela Schlederer, Eleanor Manners, Annabel Sorby-Adams, Joshua Kaggie, Ricky M. Trigg, Christopher Steel, Lucy Hare, Emily R. James, Nina Prokoph, Stephen P. Ducray, Olaf Merkel, Firkret Rifatbegovic, Ji Luo, Sabine Taschner-Mandl, Lukas Kenner, G. A. Amos Burke and Suzanne D. Turner ()
Additional contact information
Perla Pucci: University of Cambridge
Liam C. Lee: University of Cambridge
Miaojun Han: University of Cambridge
Jamie D. Matthews: University of Cambridge
Leila Jahangiri: University of Cambridge
Michaela Schlederer: Medical University of Vienna
Eleanor Manners: University of Cambridge
Annabel Sorby-Adams: Hills Road
Joshua Kaggie: University of Cambridge, Cambridge Biomedical Campus
Ricky M. Trigg: University of Cambridge
Christopher Steel: University of Cambridge
Lucy Hare: University of Cambridge
Emily R. James: University of Cambridge
Nina Prokoph: University of Cambridge
Stephen P. Ducray: University of Cambridge
Olaf Merkel: Medical University of Vienna
Firkret Rifatbegovic: CCRI, Zimmermannplatz 10
Ji Luo: National Cancer Institute, National Institutes of Health
Sabine Taschner-Mandl: CCRI, Zimmermannplatz 10
Lukas Kenner: Medical University of Vienna
G. A. Amos Burke: Oncology and Palliative Care, Addenbrooke’s Hospital
Suzanne D. Turner: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47771-x

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